Congenital heart disease associated with sporadic Kallmann syndrome

American Journal of Medical Genetics 46551-554 (1993)

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Congenital Heart Disease Associated With Sporadic Kallmann Syndrome Alan B. Cortez, Alvaro Galindo, Frederick W. Arensman, and Cornelis Van Dop Divisions of Pediatric Endocrinology (A.B.C., C.V.D.) and Pediatric Cardiology (A.G.), UCLA School of Medicine, Los Angeles, California; Humana Hospital Audubon, Louisville, Kentucky (F.W.A.)

A 17-year-old boy with Kallmann syndrome had complex congenital heart disease that included double-outlet right ventricle, d-malposition of the great arteries, right aortic arch, and hypoplastic main pulmonary artery. He had neurosensory hearing loss and mental retardation. The 7 previously reported patients with Kallmann syndrome and cardiac abnormalities were short with height 2-2 standard deviations below the mean for age (5/7), lacked a family history of Kallmann syndrome (6/6), and were mentally retarded (414). Patients presenting with Kallmann syndrome and congenital heart defects appear to represent a distinct subgroup of patients with Kallmann syndrome. The cause of this association is unclear, but may involve either auto- soma1 recessive inheritance, sporadic dominant mutation, or a shared teratogenic event during the first trimester of gestation. 0 1993 Wiley-Liss, Inc.

KEY WORDS: congenital heart disease, double-outlet ventricle, anosmia, hypogonadotropic hypogonadism, anosmia, Kallmann syndrome

INTRODUCTION Kallmann syndrome, the most common genetic form

of hypogonadotropic hypogonadism, has inheritance patterns in different pedigrees compatible with either an X-linked disorder with variable penetrance in female carriers, an autosomal recessive disorder, or an autoso- ma1 dominant disorder [McKusick, 19921. The X-linked form of the syndrome apparently results from defects in the KALIG-1 gene on the X chromosome that shares

Received for publication September 28, 1992; revision received February 1, 1993.

Address reprint requests to Cornelis Van Dop, M.D., Ph.D., MDCC 22-315, UCLA Medical Center, 10833 Le Conk Avenue, Los Angeles, CA 90024-1752.

0 1993 Wiley-Liss, Inc.

sequence homology with neural cell adhesion and axonal path-finding molecules [F'ranco et al., 1991; Bick et al., 19921. The hallmark of Kallmann syndrome is anosmia or hyposmia with congenital hypogonadotropic hypogonadism [McKusick, 19921. Other developmental abnormalities include cleft palate, neurosensory hearing loss, gut malrotation, renal agenesis, and congenital heart defects.

We describe a boy with Kallmann syndrome who had severe congenital heart disease. He shared several un- usual characteristics with previously described patients with Kallmann syndrome and cardiac abnormalities, suggesting that congenital heart disease identifies a distinct subgroup of patients with Kallmann syndrome.

CLINICAL REPORT A 17-year-old black young man with severe congenital

heart disease was referred for heart transplantation and noted to have a micropenis. He was the 1,930 g product of a term, G4P3 uncomplicated pregnancy. He had intrauterine growth retardation with length 45 cm ( - 2.2 SD) and OFC - 31.5 cm ( - 2.4 SD). Hypoglycemia was not noted during infancy. Cyanosis shortly after birth prompted cardiac evaluation. Cardiac catheterization demonstrated ventricular septal defect, atrial septal defect, double-outlet right ventricle, d-malposition of the great arteries, right aortic arch, anomalous left anterior descending coronary artery, and hypoplastic main pulmonary artery with well-formed right and left branch pulmonary arteries. At age 18 months, he received a Waterston shunt (connection of ascending aorta to right pulmonary artery). Although his cardiac status improved, limited exercise tolerance continued. At age 10 years, he underwent an attempt to close his atrial and ventricular septal defects and enlarge the right ventricular outflow tract and main pulmonary artery. A large right ventriculotomy was performed. The correc- tion was not completed due to anomalous origin of the left anterior descending coronary artery and the se- verely hypoplastic main pulmonary artery. The septal defects were not repaired, the ventriculotomy was closed and the Waterston shunt was reestablished. Due to progressive ventricular dysfunction at age 16 years, he underwent a classic Glenn anastomosis (connection of superior vena cava to right pulmonary artery) with con- comitant ligation of the azygous vein. Subsequently,

552 Cortez et al.

congestive heart failure worsened with progressive in- sufficiency of the aortic, mitral and tricuspid valves, but with normal pulmonary arteriolar resistance, and he was referred for heart transplantation.

Bilateral moderate neurosensory hearing loss was noted during infancy, and he had developmental delay with mental retardation. At age 4 years, micropenis and bilateral cryptorchidism were noted. A chorionic gonadotropin stimulation test showed an adequate rise in serum testosterone and he underwent bilateral or- chiopexies. A shortened frenulum of the tongue impair- ing speech development was treated with frenotomy. At age 10 years, cranial computed tomography docu- mented normal size, shape and position of the ventricles and sulci. The internal and external auditory canals were symmetrical with cochlear apparatus and semicir- cular canals present. Excretory urogram demonstrated normal kidney size and function with normal ureters.

On examination at age 17 years, height was 155 cm ( - 2.9 SD), weight was 31.8 kg ( - 3.5 SD), and OFC was 51 cm (>2 SD below mean for age). He had normal hair distribution, his ears were set normally, and there was no hypo- or hypertelorism. He lacked lentigines on skin, and ocular fundi were normal. He had moderate cyanosis with jugular venous distension to the angle of the jaw while sitting upright, hyperdynamic precordium, grade 2/6 systolic murmur at the left sternal border, a grade 3/6 decrescendo diastolic murmur at the left sternal border and a grade 3/6 blowing holosystolic murmur at the apex. Liver was enlarged with edge at the umbilicus. Phallic length was 3.7 cm (>2 SD below mean for a prepubertal male) with penile corpora present; soft testes (1.5 cm3 and 2.5 cm3) were in the scrotum. Several pigmented axillary and pubic hairs were noted. Olfactory sense was absent during several blinded tests using non-noxious olfactory stimuli that included or- ange juice, apple juice, coffee, and water. He was bed- ridden due to congestive heart disease.

Karyotype was 46,XY without gross cytogenetic abnormalities of the X chromosome. Luteinizing and folli- cle stimulating hormones were undetectable in serum (<2 UIL; ref. <4 U/L in prepubertal children) and testosterone concentration in serum was 0.7 nmol/L. Bone age was 14 years. Serum thyrotropin concentration was 4.3 mUL (ref. 0.3-4.7 mU/L); thyroxine concentration was 95 nmol/L (ref. 64-142 nmol/L); triiodothyronine concentration was 0.8 nmollL (ref. 1.2-3.4 nmol/L); and serum reverse triiodothyronine concentration was 1352 pmoln (ref. 77-445 pmol/L).

By history his mother had regular menses, and she had normal olfaction using non-noxious stimuli. Father was unavailable, but reportedly had normal fertility and olfaction. There was no family history of infertility or absent pubertal development.

Following successful heart transplantation, exercise tolerance improved markedly and he is now attending school. He remained anosmic. Growth rate has been -5 c d y following heart transplantation.

METHODS Standard deviation scores for height and weight were

calculated using published standards [Hammill et al., 19771.

DISCUSSION A number of endocrine disorders can produce micro-

penis in newborn infants with 46,XY genotype, including hypogonadotropic hypogonadism, testicular failure, defective androgen biosynthesis, and partial androgen resistance. In general, the association of multiple congenital anomalies with micropenis suggests genetic causes such as F’rader-Willi syndrome, Bardet-Biedl syndrome, CHARGE association, Noonan syndrome, multiple lentigines syndrome, and 49,XXXXY syndrome, several of which have been associated with congenital heart defects. Evaluation includes determina- tion of karyotype, as well as serum gonadotropins and testosterone, which are generally elevated to pubertal levels during the first several months of life.

Formation of the phallus and scrotum in the male fetus depends on fetal dihydrotestosterone during weeks 8-12 of gestation and is independent of fetal pituitary gonadotropins. In the last trimester, penile growth and testicular descent are dependent on fetal production of gonadotropins that stimulate the fetal testes. Micro- penis without hypospadias or scrota1 abnormality, undetectable serum gonadotropins, and cryptorchidism in- dicate that this young man has hypogonadotropic hypogonadism and not defective androgen biosynthesis or responsiveness.

Causes of hypogonadotropic hypogonadism other than Kallmann syndrome are unlikely in this boy. Pan- hypopituitarism is unlikely because the normal serum thyroxine level despite “sick euthyroid syndrome” (elevated reverse triiodothyronine) indicates adequate thyrotropin production. The presence of sexual hair and a low serum testosterone concentration indicates ad- renarche which depends on adequate corticotropin production. Constitutional delay of puberty in boys is not associated with micropenis or anosmia, and in most of these boys, puberty generally commences by age 17 years. The short stature prior to heart transplantation most likely resulted from his severe heart dysfunction, not growth hormone deficiency, because he had a normal growth rate following heart transplantation. The finding of anosmia confirms that Kallmann syndrome is the cause of his hypogonadotropic hypogonadism.

To determine whether patients with Kallmann syndrome and congenital heart disease share other clinical manifestations, we reviewed all reported cases (Table I). Although complete clinical histories are not available on each patient, these subjects had several manifestations uncommonly described in patients with Kallmann syndrome. Every patient in Table I lacked a family history of Kallmann syndrome; 5 of 7 patients on whom data were reported had heights 2 2 standard deviations below the mean for age, and 4 of the 8 had mental retardation (Table I). By contrast, 15 of 23 patients with Kallmann syndrome in a large series [Lieblich et al., 19821, reported a family history of Kallmann syndrome, and only one had short stature (No. 6 in Table I). In another series [Van Dop et al., 19871, short stature was present in only one of 10 patients with Kallmann syndrome. Chronic illness or intrauterine growth retardation may have contributed to short stature noted in three subjects listed in Table I (Nos. 1 ,6 , and 8). Growth hormone deficiency was excluded by testing with provo-

Heart Disease and Kallmann Syndrome 553

TABLE I. Congenital Heart Disease in Kallmann Syndrome

Height (cm) Family Mental Cardiac lesions Reference Patient Sex Age (y) (SD score) history retardation

1. F 24 151 (-2.0)

2. F 21 145 (-2.9)

3. F 38 -

4. F 38 160 (-0.6)

5. M 22 173 (-0.6)

6. F 35 142 (-3.4)

7. M 30 155 (-3.0)

8. M 17 155 (-2.9)

a -

-

No

No

No

No

No

No

Yes

-

-

-

-

Yes

Yes

Yes

Ebstein anomaly, WOW- Gauthier [1960] Parkinson- White syndrome Right aortic arch,

probable bicuspid aortic valve

2 : 1 atrioventricular block and Wenckebach block

Atrioventricular block, junctional rhythm (34 bpm)

ASD,b incomplete right bundle-branch block

Right aortic arch, left subclavian stenosis et al. [1983]

ASD, mitral valve prolapse incomplete right bundle-branch block

ventricle, ASD, ventricular septal defect, right aortic arch, malposition of

Rosenberg and Riddick 119761

Gould and Reddy [1977]

Kemmann et al. [1980]

Dimitrovski et al. [ 19821

Lieblich et al. [19821, White

Moorman et al. [1984]

Double-outlet right [This report]

great vesSeIs a Not reported. ASD, Atrial septa1 defect.

cative stimuli in the two shortest patients in Table I (Nos. 6 and 7).

Two of the patients in Table I had congenital hearing loss and a short frenulum of the tongue, in addition to an unremarkable family history, short stature, and mental retardation. This constellation of findings, including short frenulum of the tongue and hearing loss, may represent the most complete expression of this variant of Kallmann syndrome.

The differing inheritance patterns among pedigrees segregating for Kallmann syndrome [McKusick, 19921 suggest that interference with fetal development by various mechanisms can lead to subsequent anosmia and hypogonadotropic hypogonadism. The X-linked form of Kallmann syndrome results from defects in the KA- LIG-1 gene localized to Xp22.3 and deletions of this gene, either complete [Franco et al., 19911 or partial [Bick et al., 19921, can produce the disorder. Due to homology of the deduced amino acid sequence of this gene product to neural cell adhesion protein, protein kinase, and protein phosphatase, Franco et al. [1991] speculated that this gene product is required for normal migration of the embryonic cell anlagen that develop into the olfactory bulbs and hypothalamic nuclei that secrete gonadotropin releasing hormone. Linkage studies for the autosomal dominant or the presumed autosomal recessive forms of the disease are not available. Whether the latter two forms of the disease result from defects in autosomal genes involved in modulating cell migration remains unknown. Such a gene product may also be involved in modulating migration of cardiac anlagen during embryonic development of the heart, thus accounting for the association between Kallmann

syndrome and certain types of congenital heart disease. The finding that bilateral ablation of neural crest cells in occipital somites 1 and 3 of chicks causes conotruncal cardiac anomalies [Kirby et al., 19831 supports the hypothesis that defective migration of neural tissue can lead to congenital cardiac defects.

Defective neuroectodermal migration of embryonic tissues was also suggested by Johnson et al. 119831 to explain a kindred of 16 members manifesting autosomal dominant inheritance of alopecia with variable anosmia, hypogonadotropic hypogonadism, conductive hearing impairment, external ear abnormalities, micro- gnathia, cleft palate, facial asymmetry, and dental caries. One affected member had a ventricular septal defect and an infant had severe conotruncal malforma- tion of the heart. The uniform alopecia and other fea- tures present in Johnson’s pedigree, distinguish that pedigree from the patients in Table I. Johnson’s kindred provides further support for the hypothesis that various genetic abnormalities that affect embryonic cell migration can be associated with hypogonadotropic hypogonadism and anosmia.

Our patient has the most severe congenital heart defects described in association with Kallmann syndrome. The presentation, clinical course, and need for heart transplantation with potential for near-normal life un- derscore the importance of identifying coexisting anomalies that contribute to morbidity in patients with congenital heart disease. Although Kallmann syndrome is treatable, early recognition is essential for optimal out- come. The presence of a micropenis in an infant with congenital heart disease merits appropriate endo- crinologic studies and consideration of several genetic

554 Cortez et al.

syndromes. Likewise, the diagnosis of Kallmann syndrome in a child requires systematic consideration of other possible associations including congenital heart defects, mental retardation, renal defects, short stature, and congenital hearing loss.

ACKNOWLEDGMENTS We thank the March of Dimes National Foundation

for its past support and Dr. Arthur Grix for useful dis- cussions.

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A, Incerti B, Pragliola A, Meitinger T, Ballabio A (1992): Intragenic deletion of the KALIG-1 gene in Kallmann’s syndrome. N Engl J Med 326:1752-1755.

Dimitrovski C, Plaseski A, Bogoev M, Sadikario S (1982): Kallmann’s syndrome associated with atrial septa1 defect. JAMA 248: 1358-1359.

Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, Carrozzo R, Maestrini E, Pieretti M, Tailon-Miller P, Brown CJ, Willard HF, Lawrence C, Persico MG, Camerino G, Ballabio A (1991): A gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Na- ture 353:529-536.

Gauthier G (1960): La dysplasie olfacto-genitale (agenesie des lobes olfactifs avec absence de dkveloppement gonadique A la pubert4). Acta Neurovegetativa 21:345-394.

Gould L, Reddy CVR (1977): Cardiac abnormalities in a female patient with hypogonadotropic hypogonadism with anosmia. J Electrocar- diol 10:279-282.

Hammill PVV, Drizd TA, Johnson CL, Reed RB, Roche AF (1977): NCHS growth curves for children. National Center for Health Sta- tistics (DHEW publication #[PHSl78-1650; Vital and health statis- tics: series 11, #165) Hyattsville, MD.

Johnson VP, McMillin JM, Aceto T Jr, Bruins G (1983): A newly recognized neuroectodermal syndrome of familial alopecia, anosmia, deafness, and hypogonadism. Am J Med Genet 15:497-506.

Kemmann E, Conrad P, Jones JR (1980): Cardiac abnormalities in female hypogonadotropic hypogonadism with anosmia. Am J Ob- stet Gynecol 136:964-966.

Kirby ML, Gale TF, Stewart DE (1983): Neural crest cells contribute to normal aorticopulmonary septation. Science 220:1059-1061.

Lieblich JM, &go1 AD, White BJ, Rosen SW (1982): Syndrome of anosmia with hypogonadotropic hypogonadism (Kallmann syndrome). Clinical and laboratory studies in 23 cases. Am J Med 73506-519.

McKusick VA (ed) (1992): “Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phe- notypes, 9th ed.” Baltimore, MD: Johns Hopkins University Press.

Moorman JR, Crain B, Osborne D (1984): Kallman’s syndrome with associated cardiovascular and intracranial anomalies. Am J Med 77:369-372.

Rosenberg SM, Riddick DH (1976): Dynamic pituitary testing in a female with Kallman’s syndrome and associated cardiac anomaly. Obstet Gynecol 48:230-233.

Van Dop C, Burstein S, Conte FA, Grumbach MM (1987): Isolated gonadotropin deficiency in boys: Clinical characteristics and growth. J Pediatr 111:684-692.

White BJ, Rogol AD, Brown KS, Lieblich JM, Rosen SW (1983): The syndrome of anosmia with hypogonadotropic hypogonadism: A genetic study of 18 new families and a review. Am J Med Genet 15:417-435.

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Congenital heart disease associated with sporadic Kallmann syndrome