Journal für Reproduktionsmedizin und Endokrinologie – Journal of and –

Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie

Rare Syndromes Associated with Hempel M, Buchholz T J. Reproduktionsmed. Endokrinol 2009; 6 (1), 24-26

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Wir freuen uns auf Sie! Rare Syndromes in Infertility Rare Syndromes Associated with Infertility

M. Hempel, T. Buchholz

Although rare syndromes seldomly are the reason for infertility, physicians for reproductive medicine should be aware of these syndromes. The majority of syndromes can be diagnosed clinically by thorough exploration of the personal and family histories and by extensive medical examination. To confirm a genetic diagnosis, specific tests have to be carried out. If a syndrome is detected, it often explains not only the reproductive failure but also other possible disabilities, leading to a specific therapy and accurate genetic counseling of the affected, patient and his family. J Reproduktionsmed Endokrinol 2009; 6 (1): 24–6. Key words: hypogonadotropic , maldescended testes, primary infertility, syndromes, genetic counseling

„„„ Introduction • Rare syndromes associated with mal- because sometimes patients with the descended testes Kallmann syndrome are not aware that Infertility is not commonly associated • Rare syndromes associated with pri- they have . Additional symp- with the occurrence of genetic syn- mary infertility. toms include eunuchoidism, cleft lip/ dromes [1]. Therefore, infertility work- palate, reduced hearing ability, unilat- up does not center on the detection of eral agenesis of a kidney, brachydactyly, rare syndromes. However, these syn- „„„ Rare Syndromes Associa- synkinesia, and agenesis of the corpus dromes can be found through a detailed ted with Hypogonadotro- callosum. and targeted personal and family history pic Hypogonadism examination, including a three-genera- Autosomal dominant, X-chromosomal tion pedigree, and through an accurate Hypogonadotropic hypogonadism causes recessive and autosomal recessive in- clinical examination. If a syndrome is infertility, which can be successfully heritance of the Kallmann syndrome has suspected, further investigations should treated by stimulation. been described (Tab. 1). In affected be initiated. There are a few syndromes which have families, the pattern of inheritance can the leading symptom of hypogonado- be distinguished according to the pedi- More than 70 syndromes associated with tropic hypogonadism. gree. in the KAL1 gene lo- infertility have been found so far. The cated on the short arm of the X chromo- majority of these syndromes is ex- Kallmann syndrome (olfactogenital syn- some have been found in 5–10 % of male tremely rare and related to severe mal- drome, anosmia with hypogonadotropic Kallmann patients. Mutations in the formations and mental retardation. Due hypogonadism) occurs in males with an FGFR1 gene have been detected in 5– to their handicaps infertility is not their incidence of 1:8000. Females can also be 10 % of autosomal dominant Kallmann main problem because mostly these pa- affected, but less frequently with an inci- syndrome patients. More infrequent mu- tients do not consider family planning. dence of 1:40,000 [3]. Cardinal symp- tations in the PROKR2 gene (~5 %) and In some syndromes, however, infertility toms of the Kallmann syndrome are the the PROK2 gene (< 5 %) have also been may be the initial obvious symptom [2]. inability to smell and hypogonadotropic revealed leading to the autosomal domi- Other symptoms can be minor and are hypogonadism. The patient has to be nant Kallmann syndrome. There is at not easily recognizable or will develop asked if he has difficulty in smelling least one more gene locus suspected of later in life.

It is not the purpose of this article to list Table 1: Molecular genetics and phenotypic association in the Kallmann syndrome all syndromes which are accompanied by infertility. Some examples of rare but X-linked recessive Autosomal dominant Autosomal recessive widely recognizable syndromes are de- Kallmann syndrome Kallmann syndrome Kallmann syndrome scribed here to illustrate the importance in KAL1 gene Mutation in FGFR1 gene Gene loci unknown of the medical history and examination (5–10 %) (5–10 %) Deletion of KAL1 gene Mutation in PROKR2 gene of the patient. (infrequent) (5 %) Mutation in PROK2 gene Among rare syndromes associated with (< 5 %) infertility it is helpful to differentiate be- Delayed pubertal development, Cleft lip/palate, oligodontia, tween: , maldescended digit malformation, • Rare syndromes associated with hypo- testes, synkinesia, unilateral synkinesia, agenesis of gonadotropic hypogonadism corpus callosum

Received: January 8, 2009; accepted after revision: February 3, 2009 From the Institut für Humangenetik, Technische Universität München, Germany Correspondence: Dr. med. Maja Hempel, Institut für Humangenetik, Technische Universität München, D-81675 München, Trogerstraße 32; e-mail: [email protected]

24 J Reproduktionsmed Endokrinol 2009; 6 (1)

For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Rare Syndromes in Infertility

Table 2: Testing algorithm in the variability of Bardet-Biedel syndrome is cranial dysostosis (hypoplasia of the cla- Kallmann syndrome very high. viculae, craniosynostosis), Bloom’s syn- drome (, teleangiectatic ery- In family cases thematous skin lesions, high risk for ma- In X-linked pattern of inheritance „ Rare Syndromes Associa- lignancies), and Russel-Silver syndrome 1. Sequencing of KAL1 gene ted with Maldescended (short stature, relative , 2. Deletion screening of KAL1 gene distinctive face, hemihypertrophy) [10]. In autosomal dominant pattern of inheritance Testes 1. Sequencing of FGFR1 gene These syndromes are usually detected 2. Sequencing of PORKR2 and PROK2 gene There are a number of syndromes associ- early in infancy. However, because these ated with maldescended testes. One ex- patients are not severely handicapped, In isolated cases ample is the Noonan syndrome in males they may desire children and therefore Male (pterygium colli syndrome, male Turner seek reproductive counseling for infer- 1. Sequencing of KAL1 gene 2. Sequencing of FGFR1 gene syndrome). This syndrome is character- tility problems. 3. Sequencing of PROKR2 and PROK2 gene ized by a (espe- Female cially pulmonary valvular stenosis, dys- 1. Sequencing of FGFR1 gene plastic pulmonary valve, and hyper- „ Rare Syndromes Associa- 2. Sequencing of PROKR2 and PROK2 gene trophic ), short stature, ted with Primary Infertility and a typical malformation contributing to this syndrome, especially ( in cranial and pectus Primary Ciliary Dyskinesia (PCD) is a for the autosomal recessivly inherited excavatum in the caudal part of the ster- rare entity caused by congenital defects Kallmann syndrome [3–5]. The algo- num). Furthermore, these patients ex- in cilia, which includes the immotile rithm for depends on the hibit a typical facial dysmorphism in- cilia syndrome, Kartagener syndrome, inheritance pattern and gender (Tab. 2). cluding , , down- ciliary dysmotility, and primary orienta- In males with sporadic Kallmann syn- slanting palpebral fissures, deep-set and tion defects. Main symptoms of PCD are drome or patients with suspected X- posterior rotated ears, short and broad recurrent and persistent rhinitis, nasal linked inheritance, the KAL1 gene should neck, and low posterior hair line. Some, polyps, recurrent ear infections, tym- be sequenced first. In females with the but not all patients suffer from mild to panosclerosis, bronchiectasis, and infer- sporadic Kallmann syndrome and pa- moderate mental retardation, depending tility. Situs inversus occurs in 50 % of tients with an autosomal dominant pat- on the underlying genetic defect [7–9]. patients with PCD, named Kartagener tern of inheritance, KAL1 gene analysis Infertility is not the leading symptom of syndrome. Additionally, PCD patients can be omitted. Instead, the order of gene Noonan syndrome but may occur as a may suffer from ceratoconus, glaucoma, sequencing should be as follows: first result of untreated maldescended testes. and myopia as well as from malforma- the FGFR1 gene, secondly the PROKR2 With an incidence of 1:1000 to 1:2500 in tions of the brain, skeleton, and kidney gene, and thirdly the PROK2 gene. This newborns, Noonan syndrome is one of [11]. The prevalence has been estimated is also recommended for males with the the more common syndromes and there- between 1:3000 and 1:20,000 depending sporadic Kallmann syndrome in whom fore a male Noonan patient is more on the inclusion criteria of the PCD defi- no KAL1 gene mutation was found [6]. likely to be found in a consultation for nition [12, 13]. infertility. The following further examples of syn- The inheritance of PCD is autosomal re- dromes associated with hypogonado- Noonan syndrome is inherited in an au- cessive in the majority of cases. Linkage tropic hypogonadism are usually recog- tosomal dominant pattern. Mutations in analyses have discovered at least nine nized early in infancy, but these patients four genes have been identified so far: gene loci up to now. Five of those have can reach reproductive age. the PTPN11 gene (50 %), SOS1 gene been identified so far: DNAH5 (30 %), (10–15 %), KRAS gene (5 %), and DNAI1 (10 %), TXNDC3 (two case re- Prader-Willi syndrome is suspected in RAF1 gene (3–17 %). At least one more ports), DNAH11 (one patient and one the first weeks of life due to feeding gene is likely to contribute to this syn- family report), and DNAI2 (three case problems and severe muscular hypo- drome. If Noonan syndrome is suspected reports). Defects in these genes result in tonia. Later in life patients display short in a patient with infertility, genetic test- loss of function of the primary ciliary stature, obesity, and mental retardation. ing is required, starting with PTPN11 apparatus which leads to an abnormal is character- gene sequencing, followed by SOS1, ciliary structure and function, frequently ized by low and high phospho- KRAS and RAF1 gene sequencing. followed by the symptoms described rus serum levels, short stature, and short There is a genotype-phenotype correla- above. For diagnosis of PCD, a biopsy of metacarpal IV. Depending on the sever- tion. The majority of patients with an the respiratory epithelium is necessary to ity of the metabolic disturbance, differ- SOS1 gene mutation shows a normal detect specific ciliary ultrastructural ent types of pseudohypoparathyroidism development and growth in contrast to defects and/or impairments of the ciliary have been classified. patients with a PTPN11 gene mutation motility using transmission electron who mostly display the full phenotype microscopy and high-speed videomicro- Bardet-Biedl syndrome patients usually [7–9]. scopy. In the case of abnormal ciliary suffer from obesity, retinitis pigmentosa, ultrastructure and/or ciliary beat fre- and renal malformation. Most patients Other syndromes with maldescended quency, testing for DNAH5 and DNAI1 show postaxial polydactyly. The clinical testes leading to infertility are Cleido- mutations is recommended [14]. But in

J Reproduktionsmed Endokrinol 2009; 6 (1) 25 Rare Syndromes in Infertility

Table 3: Phenotype and molecular genetics of 1 „ Practical Aspects Mild DM1 Classic DM1 Congenital DM1 Awareness of rare syndromes is very Symptoms Mild myotonia Myotonia Muscle important in patients with unex- Cataract Muscle weakness Respiratory insufficiency Infertility Cataract Facial muscle weakness plained infertility. Rare syndromes Diabetes mellitus Cardiac arrhythmia Mental retardation can be detected by a detailed medical Frontal balding Symptoms of classic history including personal history, Infertility DM1 in adults Diabetes mellitus medical data, associated disabilities, Others family history, and medical examina- Age of onset 20 to 70 years 10 to 30 years Birth tion. Consultations of a human ge- CTG repeat 50 to ~200 ~100 to ~1000 > 2000 neticist help to clarify the speculated expansion syndrome. The diagnosis can often Life expectancy 60 years to normal 45–55 years 45 years be confirmed or ruled out by specific genetic testing. The care for these patients needs close cooperation be- tween several specialists. 60 % of PCD patients, the gene defect peat expansion from generation to gen- cannot be identified. eration. DM1 can be suspected by a de- References: tailed query of medical personal and 1. Diemer T, Desjardins C. Developmental and genetic disorders Males with myotonic dystrophy 1 (Mor- family history and an accurate medical in spermatogenesis. Hum Reprod Update 1999; 5: 120–40. bus Curschmann-Steinert, Dystrophia examination. To confirm the diagnosis 2. Garcia de Andoin N, Echeverria J, Cobo AM, Rey A, Paisán L, myotonica 1, DM1) may also suffer from molecular testing of the CTG repeat ex- López de Munain A. A neonatal form of Steinert’s myotonic dys- trophy in twins after in vitro fertilization. Fertil Steril 2005; 84: primary infertility. In some patients, this pansion in the DMPK gene is mandatory 756. even is the initial obvious symptom [1]. [17]. 3. Hu Y, Tanriverdi F, MacColl GS, Bouloux PM. Kallmann’s syn- drome: molecular pathogenesis. Int J Biochem Cell Biol 2003; 35: DM1 is a multisystem disorder affecting 1157–62. the skeletal and smooth muscles, the „ Conclusion 4. Cadman SM, Kim SH, Hu Y, González-Martínez D, Bouloux PM. heart, the eyes, and the endocrine and Molecular pathogenesis of Kallmann’s syndrome. Horm Res 2007; 67: 231–42. central nervous systems. According to These examples of rare syndromes as- 5. Layman LC. Genetics of human hypogonadotropic hypogonad- the phenotype, three partially overlap- sociated with infertility show that they ism. Am J Med Genet 1999; 89: 240–8. ping types have been classified: mild, can be detected by a detailed medical 6. Sato N, Katsumata N, Kagami M, Hasegawa T, Hori N, Kawakita S, Minowada S, Shimotsuka A, Shishiba Y, Yokozawa M, Yasuda T, classic, or congenital DM1 (Tab. 3). The history and through medical examina- Nagasaki K, Hasegawa D, Hasegawa Y, Tachibana K, Naiki Y, main symptoms of all types of DM1 are tion. The history should include the per- Horikawa R, Tanaka T, Ogata T. Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth fac- myotonia (sustained muscle contraction) sonal history (including development, tor 1 (FGFR1, or KAL2) in five families and 18 sporadic pa- and posterior subcapsular cataract. The education, etc.), medical data (opera- tients. J Clin Endocrinol Metab 2004; 89: 1079–88. 7. Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, majority of patients show a typical myo- tions, frequent infections, etc.), associ- Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A, Rauch A. Geno- pathic and expressionless face [15]. ated disabilities (hearing loss, inability type-phenotype correlations in Noonan syndrome. J Pediatr 2004; Muscular weakness, frontal balding, car- to smell, etc.), and a family history with 144: 368–74. 8. Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy diac arrhythmias, fatigue, , a three-generation pedigree. Clinical in- A, Pandit B, Oishi K, Martinelli S, Schackwitz W, Ustaszewska A, constipation or diarrhea, and diabetes vestigations by and/or consultations of Martin J, Bristow J, Carta C, Lepri F, Neri C, Vasta I, Gibson K, Curry CJ, Siguero JP, Digilio MC, Zampino G, Dallapiccola B, Bar-Sagi D, mellitus are additional symptoms which a human geneticist help to clarify the Gelb BD. Gain-of-function SOS1 mutations cause a distinctive form may occur in all types of DM1, but less speculated syndrome and lead to a diag- of Noonan syndrome. Nat Genet 2007; 39: 75–9. frequently in the mild type. Congenital nosis. 9. Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt DM1 is the most severe phenotype char- I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD. PTPN11 mutations in Noonan syndrome: acterized by muscular hypotonia and Although these syndromes are rare in molecular spectrum, genotype-phenotype correlation, and respiratory problems already present in patients with infertility, awareness is phenotypic heterogeneity. Am J Hum Genet 2002; 70: 1555–63. the neonatal period. Surviving children very important for physicians of repro- 10. German J. Bloom’s syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet 1997; 93: 100–6. develop mental retardation and symp- ductive medicine so that the affected 11. Teknos TN, Metson R, Chasse T, Balercia G, Dickersin GR. New toms of classical DM1 [16]. patients and their families can be ad- developments in the diagnosis of Kartagener’s syndrome. equately counseled by human geneti- Otolaryngol Head Neck Surg 1997: 116: 68–74. 12. Afzelius BA. Genetics and pulmonary medicine. 6. Immotile cilia DM1 follows an autosomal dominant cists. Genetic consultation should com- syndrome: past, present, and prospects for the future. Thorax 1998; pattern of inheritance. The underlying prise detailed information about the re- 53: 894–7. 13. Meeks M, Bush A. Primary ciliary dyskinesia (PCD). Pediatr genetic defect is based on the expansion spective syndrome, the availability of Pulmonol 2000; 29: 307–16. of CTG repeats in the DMPK gene. specific therapies and programs for pre- 14. Holzmann D, Ott PM, Felix H. Diagnostic approach to primary More than 50 CTG repeats result in ventive care. This should also include ciliary dyskinesia: a review. Eur J Pediatr 2000, 159: 95–8. 15. Gharehbaghi-Schnell E, Finsterer J. Myotonic dystrophy: mo- DM1. The expansion correlates with counseling about the possible risk for lecular genetics and diagnosis. Wien Klin Wochenschr 1998; 110: the phenotype (Tab. 3). An increased family members and the risk for own 7–14. CTG repeat expansion is associated affected children. Treatment of these 16. Gharehbaghi-Schnell EB, Finsterer J, Korschineck I, Mamoli B, Binder BR. Genotype-phenotype correlation in myotonic dystrophy. with the severity of the disease and an patients mostly requires close coopera- Clin Genet 1998; 53: 20–6. earlier onset of symptoms. Alleles may tion between several professions like re- 17. International Myotonic Dystrophy Consortium. New nomencla- ture and DNA testing guidelines for myotonic dystrophy type 1 expand during gametogenesis resulting productive specialists, geneticists, endo- (DM1). The International Myotonic Dystrophy Consortium (IDMC). in transmission of an increased CTG re- crinologists, and others. Neurology 2000; 54: 1218–21.

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