242 Case reports J Med Genet: first published as 10.1136/jmg.13.3.242 on 1 June 1976. Downloaded from indicate any feature that can be regarded as charac- due to teristic of trisomy 9q. However, when more cases are reported a syndrome may become recognizable. XY gonadal absence syndrome* We thank Margaret Sinclair, Mary Sturrock, and Summary. A 21-year-old pheno- Dorothy Mentiply for their help. typic with a 46,XY chromosome MICHAEL FAED, JANET ROBERTSON, SHEILA complement and gonadal absence was BROWN, P. J. SMAIL, and R. D. MUCKHART studied. Basal levels ofplasma immuno- The Cytogenetics Laboratory, Department of reactive (LH), Pathology, Dept. of Child Health, and Dept. of follicle stimulating hormone (FSH), Orthopaedic and Traumatic Surgery, University of , and oestradiol were meas- Dundee ured. Pituitary sensitivity and reserve was evaluated by the exogenous admin- Note added in proof istration of synthetic luteinizing Since submitting3this report two cases of trisody 9q hormone-releasing hormone. The epi- have been described by Turleau et al (1975). The sodic release of gonadotrophins was similarity in the appearance of these patients and of ours assessed by measuring plasma LH and is striking. FSH in plasma samples obtained at 20- minute intervals for a 4-hour period. Endocrine gonadal function was evaluated REFERENCES by a stimulation test with human Arrighi, F. E. and Hsu, T. C. (1971). Localisation of heterochro- matin in human chromosomes. Cytogenetics, 10, 81-86. chorionic gonadotrophin for 3 days. The Baccichetti, C. and Tenconi, R. (1973). A new case of trisomy for results showed: a) persistently raised the short arm of No. 9 chromosome. Journal of Medical Genetics, 10, 296-299. plasma levels of both LH and FSH; b) Bobrow, M., Madan, K., and Pearson, P. L. (1972). Staining of a some specific regions of human chromosomes, particularly the pulsatile pattern of release of both

secondary constriction region of no. 9. Nature New Biology, 238, gonadotrophins and a normal pituitary copyright. 122-124. Bowen, P., Ying, K. L., and Chung, G. S. H. (1974). Trisomy 9 response to the synthetic hypothalamic mosaicism in a newborn infant with multiple malformations. decapeptide; and c) extremely low levels J3ournal of Pediatrics, 85, 95-97. Dinno, N. D., Silvey, G. L., and Weisskopf, B. (1974). 47,XY,t of circulating testosterone and oestradiol (9p+ ;llq+) in a male infant with multiple malformations. with a lack of response to the HCG Clinical Genetics, 6, 125-131. Feingold, M. and Atkins, L. (1973). A case of trisomy 9. Journal stimulus. A careful exploratory laparo- of Medical Genetics, 10, 184-187. tomy of uterus, Fal- http://jmg.bmj.com/ Fujita, H., Tatsuo, A., Yamamoto, K., and Furuyama, J. (1974). revealed absence Possible complex translocation t(9;14;13)(ql2;pl ;q31) in a mother lopian tubes, the Miillerian portion of of a child with 9p-trisomy syndrome. Human Genetics, 25, 83-92. Haslam, R. H. A., Broske, S. P., Moore, C. M., Thomas, G. H., and the , and . No Wolffian Neill, C. A. (1973). Trisomy 9 mosaicism with multiple con- derivatives were found. A dissociation genital anomalies. J'ouirnal of Medical Genetics, 10, 180-184. Newton, M. S., Cunningham, C., Jacobs, P. A., Price, W. H., and of testosterone and the so-called Jost Fraser, I. A. (1972). Chromosome survey of a hospital for the substance effects during early sexual mentally subnormal Part 2: autosome abnormalities. Clinical Genetics, 3, 226-248. development may explain the findings in Podruch, P. E. and Weisskopf, B. (1974). Trisomy for the short this unusual abnormality. The term on September 24, 2021 by guest. Protected arms of chromosome 9 in two generations, with balanced trans- locations t(l5p + ;9p -) in three generations. Journal of Pedia- 'XY gonadal absence syndrome' includ- trics, 85, 92-95. to this Rethore, M. O., Hoehn, H., Rott, H. D., Courtier, J., Dutrillaux, B. ing five types of variants designate and Lejeune, J. (1973). Analyse de la trisomie 9p par denatura- condition is proposed. tion menagee. A propos d'un nouveau cas. Human Genetics, 18, 129-138. Seabright, M. A. (1971). A rapid banding technique for human Agonadism in phenotypically female individuals chromosomes. Lancet, 2, 971-972. Turleau, C., de Crouchy, J., Chavin-Colin, F., Roubin, M., with a 46,XY chromosome complement results in Brissaud, P. E., Repesse, G., Safar, A., and Borniche, P. (1975). an incomplete form ofmale pseudohermaphroditism. Partial trisomy 9q: a new syndrcme. Human Genetics, 29, 233- 241. This clinical condition has been recently designated Zaremba, J., Zdienicka, E., Glogowska, I., Abramowicz, T., and Taracha, B. (1974). Four cases of 9p trisomy resulting from a balanced familial translocation (9:15)(ql3qll). Clinical picture * This study was supported in part by grants from the World and cytogenetic findings. J'ournal of Mental Deficiency Research, Health Organization (WHO) and International Development 18, 153-190. Research Center (IDRC). Case reports 243 J Med Genet: first published as 10.1136/jmg.13.3.242 on 1 June 1976. Downloaded from as the XY gonadal agenesis syndrome (Sarto and were assayed in duplicate. Results were expressed as Opitz, 1973). Parks et al (1974) have reviewed the nanograms (ng) of LER-907 /ml. The coefficients of clinical course of the reported cases of patients with variation of these assays were less than 12%. LH and this syndrome and pointed out the importance of FSH values for normal males are 47.0+6 and 160.0+ the 8 ng/ml, respectively. endocrine gonadal studies, and suggested Plasma testosterone and oestradiol were measured by possibility that this syndrome represents a form of hapten-RIA without chromatography as previously dysgenetic male pseudohermaphroditism with a reported (Pirke, 1973; Korenman et al, 1974). The scant amount of functioning testicular tissue. sensitivity of these assays was 50 picograms (pg)/ml. Very recently we have demonstrated in such an Testosterone and oestradiol values for normal males are adult patient a complete lack of testicular steroid- 4.3 + 1.5 ng/ml and 45 ± 10 pg/ml, respectively. ogenesis, with a concomitant increase in the Synthetic LH-releasing hormone (LH-RH) was circulating levels of pituitary gonadotrophins (Rios kindly supplied by Hoechst Farbwerke, A.G. Buccal et al, 1974). smear for chromatin X detection and chromosome To our knowledge only 10 patients with this studies were carried out according to the procedure syndrome have been reported and endocrine described by Moorhead et al (1960). functional studies have been performed in only one Functional endocrine studies. Pituitary gonado- child and one adult. Therefore, we felt it to be of trophin function was evaluated by measuring LH and interest to report the pituitary and gonadal dynamic FSH in plasma samples obtained through an indwelling studies performed in a 21-year-old male pseudo- intravenous catheter at 20-minute intervals during a 4- patient with gonadal absence. hour period. Pituitary reserve and responsiveness were variability in the and assessed by giving an IV bolus of 100 ,ug synthetic Because of the large internal LH-RH and measuring plasma LH and FSH before, external genitalia in the reported cases, which and 30 and 60 minutes after injection. suggests different pathogenic mechanisms, we Gonadal endocrine function was evaluated by measur- think it is convenient to designate this unusual ing plasma immunoreactive testosterone and oestradiol abnormality as the 'XY gonadal absence syndrome', before, during, and after administration of intramuscular including five types ofvariants. HCG 5000 IU/day for 3 consecutive days. Afterwards the patient was subjected to an exploratory laparotomy.

Clinical summary copyright. Results A 21-year-old phenotypic female was referred to the genetic department because of primary amenorrhoea The basal levels of plasma LH and FSH in this and absence of pubic and axillary hair, in spite of patient were found to be persistently raised, as oestrogen-progesterone therapy for 4 years. The compared with values found in normal males. LH patient had noted slight breast development and fat mean levels were 262.58 ng/ml (range: 150-399) deposit in the hips after treatment. She was the third while FSH mean levels were 601.53 ng/ml (range: child in a four-member family, all of whom were 380-760). http://jmg.bmj.com/ apparently normal, and was the product of an un- A pulsatile pattern of release of both gonado- complicated pregnancy and delivery. The sex of rear- to in ing and psychological orientation were female. Physical trophins (Fig. 1) similar that found patients examination revealed a phenotypic female with a with hypergonadotrophic hypogonadism of different eunuchoid habit. Her height was 173 cm, span 173 cm, origins (Root et al, 1972; Yen et al, 1972; Santen vertex-pubis 79 cm, and weight 76 kg. Neither and Bardin, 1973; Kelch et al, 1973; Perez- hirsutism nor body hair was detected. Gynaecological Palacios et al, 1974) was observed. The plasma examination showed prepubertal external genitalia, with levels of FSH were always higher than those of LH, hypoplastic labia and normal . The vagina was the ratio of FSH/LH being 2.28. A lack of on September 24, 2021 by guest. Protected 2.5 cm deep and ended blindly. Uterus and adnexa coincidence of the secretory episodes of both could not be palpated and no masses were detected in the gonadotrophins was also observed. inguinal canals or in the labia. Buccal smears did not show chromatin X bodies, and cytogenetic studies The IV administration of LH-RH induced a revealed a 46,XY chromosome constitution. Pelvic significant and even exaggerated increase in the pneumography showed absence of internal genitalia, and circulating levels of LH (up to 2256.0 ng/ml). A repeated urocytograms revealed lack of oestrogenic and concomitant increase on the plasma levels of FSH progestational activity. though to a lesser extent (up to 1340.0 ng/ml) was also observed (Fig. 1). These data clearly Material and methods demonstrate an adequate pituitary responsiveness to Plasma LH and FSH were measured by double- the exogenous stimulation in spite of the already antibody radioimmunoassays (RIA) as previously raised basal levels of plasma gonadotrophins. An described by Mendoza et al (1972). Plasma samples identical pituitary response has been reported to 244 Case reports J Med Genet: first published as 10.1136/jmg.13.3.242 on 1 June 1976. Downloaded from 3000i absence of Miullerian and Wolffian derivatives as LH-RH well as gonadal tissue. 2000 Discussion -1000- The non-mosaic 46,XY individual reported herein represents a form of male pseudoherma- c phroditism caused by absence of gonads. The patient's phenotype though of the female type lacked o 500* breast development and sexual hair growth, CL indicating absence of steroid sex hormone pro- duction. Further support for this concept was furnished by the finding of almost undetectable levels of plasma testosterone and oestradiol, with concomitant raised levels of plasma pituitary gonadotrophins. I I I * 2 II- 505 2 3 4 5, Complete absence oftesticular endocrine function Time (h) was shown by the lack of testosterone production FIG. 1. Episodic fluctuations of plasma LH,and FSH. Blood after HCG stimulation. As a result ofthis hormone samples were drawn at 20-minute intervals duringg 4 hours. There- synthesis impairment, the circulating levels of both after 100 lsg synthetic LH-RH was IV administere.d and the response evaluated by the increase of the LH and FSH plgasma levels. LH and FSH exhibited frequent fluctuations ofgreat amplitude suggesting periodic secretion episodes. In addition, the significant response in terms of plasma LH and FSH observed after LH-RH _ 20- HCG 5000 IU/doy -n ~ - stimulus confirms the anatomical-functional aE integrity of the anterior pituitary. These data w 15 demonstrated normal function of the hypothalamic- I pituitary axis in the absence of gonadal functional tissue. copyright. 8 The absence ofMiillerian and Wolffian derivatives O and gonadal tissue observed at laparotomy confirmed the results of the hormonal studies. These data i AG demonstrated a clear dissociation of effects of the -I 0 I 2 3 Jost substance and testosterone during early Days intrauterine life. Thus, lack of circulating testo- FIG. 2. Basal levels of plasma immunoreactive testosterone of the sterone at that time of development explains the http://jmg.bmj.com/ patient with XY gonadal absence syndrome. i (AG) after gonadal stimulation with HCG was obserlaedk. oTresticnlare female phenotype and external genitalia observed at gonadal response (mean ± SD) in normal individLuaLs (n = 15) under birth as well as the absence of breast development, identical conditions is also depicted. sexual hair growth, and signs of virilization at . The absence of internal genitalia can be explained either by the early effect of the Miillerian occur in other hypergonadotrophic patients (Kastin, inhibitory substance with later testicular re-

Gual, and Schally, 1972; Wagner et al, 1973; Yen absorption or by the absence of the gonadal anlagen. on September 24, 2021 by guest. Protected et al, 1973; Scaglia et al, 1974). A great variability in both the internal and Plasma levels of circulating testosterone were external genitalia has been found in the few patients extremely low (0.06 ng/ml) and rn esemble those studied with this abnormality, and genetic and observed in newborns, and plasma o(estradiol levels endocrine studies have been carried out only were below the limit of sensitivity of"the employed recently (Overzier and Linden, 1956; Schoen, King, assay. After HCG administrationi, a lack of and Baritell, 1955; Philipp, 1956; Chaptal and response in terms of plasma testoster4 one increase as Pages, 1958; Harnden and Stewart, 1959; Dewhurst, compared with the response obsenved in normal Paine, and Blanck, 1963; Overzier, 1963; Emson males was found (Fig. 2). These dalta clearly show and Buckwold, 1965; Rath, Scheibenreiter, and the absence of functional Leydig cells in this Thalhammer, 1968; Parks et al, 1974; Rios et al, patient. 1974). These heterogeneous characteristics suggest The exploratory laparotomy revealed complete that different pathogenic mechanisms during Case reports 245 J Med Genet: first published as 10.1136/jmg.13.3.242 on 1 June 1976. Downloaded from

XY GO NA DAL A BS ENCE S Y N D R O M E

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tt tt ROVRMA% ., T.O. -1 tt^L IN DUCTS Of *orlttEttE, F Srl TU EA W OLF F@ U LL WO L F f A T OFS 'ULL E . HuLEtA sr^ucU"E* 5 us STUCTES S . 'CrU"t'ENS 5ST RUCTUR d STR,CTU ^ E S 4- c INTERNAL 99'a D GENITALIA ABSENT |f

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PHENOTYPEI 9 9 |'

ABSENT 0 DE VELSET ABSENT ABSENT ABSENT ABSENT R- PLASMA | UN DETECTABLE UN DETECTABLE LOW LOW LOW D C. MCG SnMUJATION NEGATIVE NEGATIVE NEGATIVE OR SLIGHTLY POSITIVE POSITIVE OR NEGATIVE POSITIVE OR NEGATIVE TEST 0 PtASMA GONAGOTRO- ELEVATED ELEVATED ELEVATED OR SUGHTLY ELEVATEOI ELEVATED OR SLIGHTLY ELEVATED ELEVATED RN DS I____I__ FIG. 3. Theoretical forms of the XY gonadal absence syndrome indicating possible pathogenic mechanisms during intrauterine life and phenotypic expression at birth and after puberty. The patient reported in this paper belongs to the incomplete agonadism type I form. The forms 'true agonadism' and 'incomplete agonadism type II' have not yet been described. (T=testosterone; JS=Jost substance.)

intrauterine life may result in the clinical features of syndrome in two sibs, the pattern of inheritance, if copyright. this syndrome. Therefore, we should like to any, remains to be ascertained. propose the term 'XY gonadal absence syndrome' to designate this abnormality. The syndrome is We wish to thank Dr T. Morato for testosterone defined as the absence of gonadal tissue in adult- determinations and Dr P. Santos for his collaboration. Purified pituitary gonadotrophins and antisera were hood in individuals with an XY chromosome kindly fumished by the National Institutes of Arthritis, complement. Since gonadal agenesis or gonadal Metabolic and Digestive Diseases (NIAMDD), USA. occur, term http://jmg.bmj.com/ reabsorption may the absence rather HCG was a gift of Organon Mexicana. than agenesis seems to be more descriptive. This syndrome theoretically includes five different S. KOFMAN ALFARO, D. SAAVEDRA 0., forms (Fig. 3) with a whole spectrum going from and G. PtREZ-PALACIOS* the complete absence of gonadal function during S. OCHOA, H. SCAGLIA, embryonic differentiation (true agonadism) to fetal Genetics Laboratory, Pathology Unit, Hospital gonadal function integrity () (Kirschner, General, S. S. A., School of Medicine Universidad Jacobs, and Fraley, 1970; Kolodny et al, 1971), Nacional Autonoma de Mexico and Department passing through the two types of incomplete of Reproductive Biology, Instituto Nacional on September 24, 2021 by guest. Protected agonadism and the mixed form of agonadism. We de la Nutricion, Mexico, D. F. agree with Parks et al (1974) that the name 'true agonadism' is a misnomer if it is used for all types * Reprint requests: Dr G. Perez-Palacios, Department of Re- of gonadal absence. productive Biologv, Instituto Nacional de la Nutrici6n, Viaducto The clinical and endocrine features observed in Tlalpan y San Fernando, Mexico 22, D. F. the patient reported in this paper are identical to those found in a similar case previously reported by REFERENCEs our group (Rios et al, 1974). Both cases correspond Chaptal, J. J. and Pages, P. (1958). Sur un cas de dysgenesie gonadique avec manifestations androgeniques. Archives Franfaises to the incomplete type I form of gonadal absence. de Pediatrie, 15, 613-618. No other affected member has been found in the Dewhurst, C. J., Paine, C. G., and Blanck, C. E. (1963). An XY female with absent gonads and vestigial pelvic organs. Journal of family of most of the reported cases. However, Obstetrics and of the British Commonwealth, 70, 675- since Overzier and Linden (1956) found this 680. 246 Case reports J Med Genet: first published as 10.1136/jmg.13.3.242 on 1 June 1976. Downloaded from Emson, H. E. and Buckwold, A. E. (1965). Agonadism. Canadian Examination of the pituitary-gonadal relationship in man with Medical Association Journal, 93, 1080-1083. synthetic LH/FSH releasing hormones. In Hypothalamic Harnden, D. G. and Stewart, J. S. S. (1959). The chromosomes in Hypophysiotropic Hormones, pp. 257-270. Ed. by C. Gual and a case of pure gonadal disgenesis. British Medical 7ournal 2, E. Rosemberg. Excerpta Medica Foundation International 1285-1287. Congress Series No. 263, Amsterdam. S. Kastin, A. J., Gual, C., and Schally, A. V. (1972). Clinical ex- Yen, S. C., Rebar, R., Vandeberg, G., Naftolin, F., Judd, H., perience with hypothalamic releasing hormones. Recent Progress Ehara, Y., Ryan, K. J., Rivier, J., Amoss, M., and Guillemin, R. in Hormone Research, 28, 201-227. (1973). In Hypothalamic Hypophysiotropic Hormones, pp. 217- Kelch, R. P., Conte, F. A., Kaplan, S. L., and Grumbach, M. M. 229. Ed. by C. Gual and E. Rosemberg. Excerpta Medica (1973). Episodic secretion of luteinizing hormone (LH) in International Congress Series No. 263, Amsterdam. adolescent Yen, S. S. C., Tsai, C. C., Vandenberg, G., and Rebar, R. (1972). patients with the syndrome of gonadal dysgenesis. Gonadotropin dynamics in patients with gonadal dysgenesis. A J'ournal of Clinical and Metabolism, 36, 424-427. model for the study of gonadotropin regulation. Journal of Kirschner, M. A., Jacobs, J. B., and Fraley, E. E. (1970). Bilateral Clinical Endocrinology and Metabolism, 35, 897-904. anorchia with persistent testosterone production. New England Journal of Medicine, 282, 240-244. Kolodny, H. D., Kim, S., Sherman, L., Futterweit, W., and Benja- min, F. (1971). Anorchia. A variety of 'empty scrotum'. J7ournal of the American Medical Association, 216, 479-482. Korenman, S. G., Stevens, R. H., Carpenter, L. A., Robb, M., Niswender, G. D., and Sherman, B. M. (1974). Estradiol radioimmunoassay without chromatography. Procedure valida- tion and normal values. Journal of Clinical Endocrinology and Cervical vertebral fusion Metabolism, 38, 718-720. Mendoza, F., Perez, A. E., Reynoso, E., and Perez-Palacios, G. (Klippel-Feil) syndrome with (1972). El uso de 125 I en los procedimientos de cuantificaci6n de gonadotropinas hipofisiarias humanas. Revista de Investigacion consanguineous parents Clinica, 24, 221-233. Moorhead, P. S., Nowel, P. C., Mellman, W. J., Battips, D. M., and Hungerford, L. (1960). Chromosome preparations of leukocytes Summary. We describe a female in- cultured from human peripheral blood. Experimental Cell fant with the cervical vertebral fusion Research, 20, 613-616. (Klippel-Feil) syndrome whom we recog- Overzier, C. (1963). True agonadism. In Intersexuality, pp. 340- 345. Ed. by C. Overzier. Academic Press, New York. nized at birth because of her short neck, Overzier, C. and Linden, H. (1956). Echter agonadisinus (an- restriction ofcervical movement, and low orchisinus) bei Geschwistern. Gynaecologia, 142, 215-225. posterior hairline. X-ray examination Parks, G. A., Dumars, K. W., Limbeck, G. A., Quinlivan, W. L., showed anomalies of and between and New, M. I. (1974). True agonadism: a misnomer? J'ournal Cl,

of Pediatrics, 84, 375-380. C2-3 and C3-4; thus, we classified her as copyright. Perez-Palacios, G., Scaglia, H. E., Medina, M., Pinto-Ferreira, A. L., type II, with variable cervical fusion. At Vazquez, G., and Gual, C. (1974). Pituitary LH and FSH sec- retion and responsiveness in elderly women. In VIII Pana- 24 months she was small and manifested merican Congress of Endocrinology, Buenos Aires, Argentina hearing deficiency. The mother and (abstract No. 21). father were consanguineous with five Philipp, E. (1956). Die Fehibildungen der Keimdruese. Deutsche Medizinische Wochenschrift, 81, 1290. common ancestors four generations ago, Pirke, K. M. (1973). A comparison of three methods of measuring which resulted in a coefficient ofinbreed- testosterone in without and radio- immunoassay chromatography to a http://jmg.bmj.com/ immunoassay including thin layer chromatography. Acta ing equivalent second cousin relation- Endocrinologica (Kbh.), 74, 168. ship. The parents and grandparents Rath, F., Scheibenreiter, S., and Thalhammer, 0. (1968). Agona- were phenotypically normal, and the dismus (anorchismus) bei einem sechs Jahre Altn Kindreded. Deutsche Medizinishe Wochenschrift, 93, 633. parents were radiologically normal. This Rios, E. P., Herrera, J., Bermudez, J., Rocha, G., Lisker, R., Morato, form ofthe syndrome has previously been T., and Perez-Palacios, G. (1974). Endocrine and metabolic said to be autosomal dominant. Our studies in an XY patient with gonadal agenesis. Journal ofClinical Endocrinology, 39, 500-507. conclusion of determination by a single Root, A., De Cherney, A., Russ, D., Duckett, G., Ram6n-Garcia, C. autosomal recessive gene is evidence of and Wallach, E. (1972). Episodic secretion of luteinizing and on September 24, 2021 by guest. Protected follicle-stimulating hormones in agonadal and hypogonadal genetic heterogeneity. adolescents and adults. Journal of Clinical Endocrinology and Metabolism, 35, 700-704. Santen, R. J. and Bardin, C. W. (1973). Episodic luteinizing The syndrome which results from cervical verte- hormone secretion in man. Pulse analysis, clinical interpretation, physiologic mechanisms. J'ournal of Clinical Investigation, 52, bral anomalies (usually fusion), attributed to Klippel 2617-2638. and to Feil, encompasses the appearance of a short Sarto, G. E. and Opitz, J. M. (1973). The XY gonadal agenesis syndrome. Journal of Medical Genetics, 10, 288-293. neck, painless restriction of cervical movement, and Scaglia, H. E., Simon, J. M., Scaglia, A. N., del Papa, A., Bermudez a low posterior hairline, at least as it is generally M., Girotto, C., and Aparicio, N. J. (1974). LH-pituitary responsiveness after administration of LH-RH in amenorrheic recognized. Radiological criteria define three types, patients. Revista de Investigacion Clinica, 26, 347-353. based in the main on the number ofvertebral fusions. Schoen, E. J., King, A. L., and Baritell, A. L. (1955). Pseudo- The second type has been further divided according hermaphroditism and multiple congenital anomalies. Pediatrics, 16, 363-369. to the specific vertebrae fused. Wagner, H., Bockel, K., Hrubesch, M., and Grete, G. (1973.) The aetiology of this congenital malformation