A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in theNF1 gene

A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in theNF1 gene
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    2006 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 140A:2749–2756 (2006)  A Variable Combination of Features of Noonan Syndrome and Neurofibromatosis Type I AreCaused by Mutations in the  NF1  Gene  Ulrike Hu¨ffmeier, 1 Martin Zenker, 1  Juliane Hoyer, 1 Raimund Fahsold, 2 and Anita Rauch  1 * 1 Institute of Human Genetics, University Erlangen-Nuremberg, Erlangen, Germany  2 Clinic for Medical Genetics, Dresden, Germany  Received 16 January 2006; Accepted 20 September 2006 Signs of neurofibromatosis type 1 (NF1) and Noonansyndrome (NS), two distinct autosomal dominant disorders,occur together in patients reported as Watson syndrome(WS), neurofibromatosis-Noonan syndrome (NFNS), partialLEOPARD syndrome, NS with features of NF1, and NF1 withNoonan-like features. The molecular basis of these com-bined phenotypes was poorly understood and controver-sially discussed over several decades. Only recently, there isincreasing evidence for WS and NFNS being allelic to NF1 inthe majority of patients. In this study we describe sevennovel patients from five unrelated families with variablephenotypes of the NF1-NS spectrum which were system-atically analyzed for mutations in the disease-causing genes  NF1  for NF1 and  PTPN11  for NS. Heterozygous mutations ordeletions of   NF1  were identified in all patients, while no  PTPN11  mutation was found. The  NF1  mutation segregated with the phenotype in both familial cases. These resultssupport the hypothesis that variable phenotypes of the NF1-NS spectrum represent variants of NF1 in the majority of cases. Constitutive deregulation of the Ras pathway eitherthrough activating mutations of   PTPN11  or through hap-loinsufficiency of neurofibromin, which acts as a Ras-inactivating GTP-ase, is probably the common pathogeneticmechanism explaining the phenotypic overlap of NS andNF1.   2006 Wiley-Liss, Inc. Key words:  neurofibromatosis type 1; Noonan syndrome;mutations in  NF1 ;  PTPN11 ; Watson syndrome How to cite this article: Hu¨ffmeier U, Zenker M, Hoyer J, Fahsold R, Rauch A. 2006. A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the  NF1  gene. Am J Med Genet Part A 140A:2749–2756. INTRODUCTION Neurofibromatosis type 1 (NF1, OMIM 162200)(also known as Morbus von Recklinghausen) isdiagnosed in the presence of at least two of thefollowing symptoms: multiple cafe´-au-lait spots,neurofibromas, axillaryor inguinalfreckling,hamar-toma of the iris (Lisch nodules), optic glioma,and typical osseous findings (dysplasia of sphenoidbones and thinning of the long bones with and without pseudoarthrosis) [NIH-Consensus-statement,1988].Althoughmostpatientsshownormalcognitivefunction, learning difficulties and attention deficitdisorder occurs in up to 50% [Mautner et al., 2002]and 4%–8% show mental retardation with IQ below70 [Ozonoff, 1999]. Ninty-five percent of patients with NF1 show autosomal dominant missense ornonsense mutations, small insertions or deletions,large-scale deletions or chromosomal translocationsaffecting the  NF1  gene located in 17q11.2 [Messiaenet al., 2000]. Patients with Noonan syndrome (NS,OMIM 163950) can be recognized by their distinctfacial anomalies such as hypertelorism with down- ward slanting palpebral fissures, low set, posteriorly rotated ears, deeply grooved philtrum with high, wide peaks of the vermilion border of the upper lip,micrognathia and bulbous nasal tip, webbed neck,sternal deformity with pectus carinatum superiorly and pectus excavatum inferiorly, congenital heartdefects (mainly pulmonary valvular stenosis), andshort stature [Allanson, 1987]. NS was only recently shown to be a heterogeneous condition commonly caused by autosomal dominant missense mutationsin  PTPN11  in 12q24 [Tartaglia et al., 2001] or rarely in  KRAS   in 12p12.1 [Schubbert et al., 2006], but *Correspondence to: Dr. Anita Rauch, Institute of Human Genetics,University of Erlangen-Nuremberg, 91054 Erlangen, Germany.E-mail: arauch@humgenet.uni-erlangen.deDOI 10.1002/ajmg.a.31547  probably also in other genes from the Ras pathway.Nevertheless,  PTPN11  mutations account for up to60% of well-characterized NS patients and aresignificantly more common in patients with pulmo-nic stenosis, short stature, and thorax deformities[Zenker et al., 2004].  PTPN11  mutations are alsofound in the majority of patients with LEOPARD(multiple lentigines and cafe´-au-lait spots, electro-cardiographic-conduction abnormalities, ocularhypertelorism, pulmonary stenosis, abnormal geni-talia, retardation of growth, and sensorineural deaf-ness) syndrome (OMIM 151100), an autosomalcondition that shares several clinical features withNS [Digilio et al., 2002, 2006; Legius et al., 2002;Sarkozy et al., 2004].Conceived as a distinct entity, co-occurrence of features from NF and NS, including pulmonary valvestenosis, borderline intelligence, multiple cafe´-au-lait spots and freckling, in three unrelated families was described by Watson [1967]. Later on Allansonet al. [1991] reviewed two of the initial reportedfamilies with Watson syndrome (WS, OMIM 193520)and revealed their phenotype to also encompassshort stature, relative macrocephaly, Lisch nodules,and neurofibromas in some of the family members. As the revised phenotype enhanced the similarity between WS and NF1, molecular linkage wasperformed which supported linkage to the NF1locus. The hypothesis of allelism was furthersupported by the finding of a  NF1  in-frame tandemduplicationof42basesinexon28ofthe  NF1 geneina family with signs of WS and NS [Tassabehji et al.,1993] and a 80 kb  NF1  deletion in a patient with WS[Upadhyaya et al., 1992]. Concurrently the so-calledneurofibromatosis-Noonansyndrome(NFNS,OMIM601321) was postulated as yet another distinct entity sharing features of both NF1 and NS [Allanson et al.,1985; Kaplan and Rosenblatt, 1985; Mendez, 1985].Since then a controversial discussion was ongoing whetherNFNSisadistinctdisorder,avariantofeitherNF1 or NS, or if there is a chance association [Opitzand Weaver, 1985; Allanson, 1987; Meinecke, 1987;Stern et al., 1992; Bahuau et al., 1996, 1998; Colley et al., 1996; Carey et al., 1997; Carey, 1998]. WhileColley et al. [1996] and Bahuau et al. [1996]documented independent segregation of NF1 andNS traits in two families and Bertola et al. [2005]reported a patient with NF1 and NS features whocarried a heterozygous mutation in both  NF1  and  PTPN11 ,Careyetal.[1997]andStevensonetal.[2006]reported co-segregation of NS with mild NF1-features with a  NF1  mutation; Baralle et al. [2003]revealed NF1 mutations in two of six NFNS patients,and De Luca et al. [2005] demonstrated  NF1  muta-tionsin16of17NFNSpatientsandexcluded  PTPN11 mutations in all of them.In order to further prove the evidence, thatNoonan-likefeaturesarepartoftheclinicalspectrumcaused by   NF1  mutations, we analyzed threesporadicpatientsandtwoparent-childdoubletswithsigns of NS and NF1 for mutations in  NF1  and  PTPN11 . METHODS Thepatientswereprospectivelyrecruitedfromourgenetics counseling clinic. The age range was 9 daysto 42 years. Two patients were referred with theclinical diagnosis of NF1, one boy due to develop-mental delay, one girl due to a tumor of the tongue,andonefamilyduetoincreased nuchaltranslucency in the first trimester. The diagnosis of neurofibroma-tosis was made according to the NIH-Consensus-statement [1988]. The diagnosis of NS was madeaccording to Zenker et al. [2004] if three or morecriteria including one major criterion were present.The presence of two criteria including one majorcriterion was classified as Noonan-like phenotype,because Zenker et al. [2004] did not reveal any   PTPN11  mutation in patients showing only twocriteria. The major criteria were: (1) typical heartdefect, either pulmonic stenosis or hypertrophiccardiomyopathy; (2) typical craniofacial anomaliesof NS including hypertelorism, downward slant of palpebral fissures, and ptosis; and (3) pterygiumcolli. The minor criteria were: (1) body height SDSbelow   2 for age; (2) psychomotor retardation orspeech delay; (3) bleeding diathesis with or withoutproven abnormality of the coagulation system; (4)two out of the following additional features: thoraxdeformity,cubitusvalgus,low-setears,lowposteriorhairline, and pre- or postnatal history of lymphede-ma, or cryptorchidism; and (5) family history of NS.Three patients were sporadic cases whereas twohadoneaffectedparent.TableIgivesanoverviewof clinical findings of all patients. All index patients were screened for mutations inthecodingpartsof   PTPN11 and  NF1 bybi-directionalsequencing and tested for microdeletions of   NF1  by FISH or MLPA. The mutational analysis of   PTPN11 and  NF1  by direct sequencing was performed asdescribed previously [Fahsold et al., 2000; Zenkeret al., 2004]. With respect to microdeletions at the  NF1  locus,two color FISH analyses on metaphase chromo-somes were performed with directly labeled DNA-probes including the K11TEL,  NF1 , D17S800, and A16INTloci[Dorschner etal.,2000].InPatient7,dueto lack of respective material, MLPA of the  NF1  gene was performed instead of FISH analysis using theMRC-Holland Corp. (Amsterdam, The Netherlands)kits P081/P082 and P122. If available, parents weretested for mutations detected in the index patients. RESULTS UnambiguousclinicalsignsofNF1werepresentinall four adult patients, as well as in the 6-year-old 2750  HU¨FFMEIER ET AL.  American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a   TABLE I. Clinical Findings in Our PatientsPatient 1 2 3, son of 2 4, mother of 5 5 6 7 Age at presentation 4 years 20 years Prenatal/ 9 days/7months37 years 6 years 42 years 20 yearsHead circumference (centile) 51.8 cm (70th) 58 cm (75th–90th) 43.5 cm (10th–25th,7 months)Not determined 53 cm (97th) 59 cm (97th) 57.4 cm ( > 97th)Body height (centile) 98.6 cm (3rd–10th) 167 cm ( < 3rd) 66.5 cm (3rd–10th,7 months)162 cm (10th–25th) 115.5 cm(25th–50th)162 cm( < 3rd, scoliosis)156 cm( < 3rd, scoliosis)Minor anomaliesHigh broad forehead  þþ þ þ þ þ þ þ Frontal cowlick/sturdy hair  þ / þ  /   /   /   /   /   /  Downslanting palpebralfissures þ þ þþ þ þ þþ þ Hypertelorism (subjective)  þþ þþ þþ þþ þþ þ þ Ptosis  þþ þ   ( þ )  þ þ  Eyebrows medial thinning  þ  þ  þ   *Lisch nodules   *   *   *  þ *  þ *  þ þ Broad nasal bridge  þ þþ þ þþ þ þ þ Low set ears  þ þ þ   þ þ Posteriorly rotated ears  þ þ þ   þ þ Low posterior hair line  þ þ þ þ þ þ þ  Webbed neck  þ þþ þ þ þ þ þþ  Axillary freckling    ?   þþ þ þ þþ Inverted nipples  þ       Thoracic deformitiesBroad chest  þ þ  þ þ  þ Pectus excavatum inferior  þ þ þ þ þþ þ þ Pectus carinatum superior  þ þ þ  þ þ  Scoliosis   þ   þþ þþ þþ (operated)Cafe´-au-lait spots 5 (diameter  1.5 cm)  > 6 (diameter > 1.5 cm)8 (diameter > 6 mm)at the age of 7months > 6 (diameter > 1.5cm)Onelarge(  6  6cm), > 6 smaller ones(diameter < 1 cm);Onehypopigmentedmacule  2  4 cm > 6 (diameter > 1.5 cm) > 6 (diameter > 1.5 cm)Neurofibromas — Multiple, cutaneous,some removed — Multiple, severalremovedOf the tongue, sinceage of   1 yearMultiple, severalremovedMultiple, severalremoved, inter aliatumor at spinalcordDevelopment Remarkably delayed:spoke only few single words at the age of 4 years; slightly delayed motor skillsLow normal, worksin auto paint shopNormal Normal Normal, speechdifficulty due tolarge neurofibromaof the tongueNormal, noproblems insecondary school, works asmechanicIntelligencebelow familiarbackground,able to lead anindependent life Abnormal behavior Restless, ‘‘self-aggressive’’,temper tantrumsNone None None None None NoneHeart defect Pulmonic stenosis(resolvedspontaneously by 4 years of life) — Aortic insufficiency — — — — ( Continued  )  Am er i   c an J   o ur n al   of   M e d i   c al   G en e t  i   c s  P  ar  t   A :  D O I   1  0  . 1  0  0 2  /   a  j  m  g . a  patient, but not in the two younger children. Due tohis young age the diagnosis of NF1 in Patient 3 wasbased on the presence of multiple cafe´-au-lait spotsand typical NF1 in a first degree relative (Patient 2).Patient 1 did not fulfill the diagnostic criteria forNF1 atthe age of4 years, but showed fivesmall cafe´-au-lait spots (diameter   1.5 cm). Patients 4 and 5,mother and daughter, fulfilled only two of ourclinicalcriteriaforNSandwerethereforeconsideredNoonan-like. Patients 3, 6, and 7 each fulfilled three,and Patients 1 and 2 each fulfilled five criteria for NS(Fig. 1). While none of the index patients carried  PTPN11 mutations, all patients were found to have aheterozygous  NF1  point mutation or heterozygousdeletion of one  NF1  copy (Table I).Threeofthefiveindexpatientshadsmalldeletionspredicting a premature stop codon which eitherleads to nonsense mediated mRNA decay or atruncated non-functional protein. In Patient 2 andhisyoungsonthe mutation c.1756_1759del4in exon21 was identified. In Patient 5 the mutationc.3060delA in exon 18 was found while Patient 6carried the heterozygous mutation c.796_803del8(GTTTGGCC) in exon 6. Patient 1 had the only missensemutationdetectedinthesepatients:L1196R (c.3587T > G)inexon21.Hishealthyparentsdidnotgive their consent to be tested themselves. Patient 7 was shown by MLPA to be deleted not only for theNF1 gene, but also for the loci CRLF3 (close toproximal JJAZ1 copy), FLJ12735, CENTA2, RNF135,HCA66, JJAZ1, and LOC114659 (33 kb distally to JJAZ1). Therefore the microdeletion in Patient 7encompasses at least 1.2 Mb between the two copiesof the  JJAZ1 gene and corresponds to the commonly observed  NF1  microdeletion [Kehrer-Sawatzki et al.,2004]. DISCUSSION  Although WS and NFNS were described as distinctdisorders and were given different OMIM numbers,reexamination of two of the original familiesrevealed that not only pulmonic stenosis, borderlineintelligence, and multiple cafe´-au-lait spots, but alsomultipleLischnodules,neurofibromasinonethirdof patients, and short stature were present [Allansonet al., 1991]. The only distinction between WS andNFNS would be therefore, that NFNS patientsalthough lacking internal NF1 complications showa more classical phenotype of both, NS and NF, whereas WS patients show only a mild expression of NF and lack the typical facial appearance of NS.Nevertheless, it is not surprising, that both syn-dromes, WS and NFNS, were recently shown to becommonly associated with  NF1  mutations [Upad-hyayaetal.,1992;Tassabehjietal.,1993;Careyetal.,1997; Baralle et al., 2003; Stevenson et al., 2006].In addition, also a 32-year-old patient with the     F   u   r   t    h   e   r    fi   n    d    i   n   g   s    M   e   c    k   e    l    d    i   v   e   r   t    i   c   u    l   a    C   o   r   n   e   a    l    i   r   r   e   g   u    l   a   r    i   t   y ,   a   m   e   t   r   o   p    i   a ,   u   m    b    i    l    i   c   a    l    h   e   r   n    i   a ,   u   r   e   t    h   r   a    l   v   a    l   v   e   s    A   s   t    i   g   m   a   t    i   s   m  —    E   n    l   a   r   g   e    d   t   o   n   g   u   e ,    l   a   r   g   e   e   p    i    d   e   r   m   a    l   n   e   v   u   s   a   t   t    h   e   a   n   t   e  -   r    i   o   r   n   e   c    k  —    H   y   p   e   r   o   p    i   a    F   u   r   t    h   e   r   g   e   n   e   t    i   c   t   e   s   t   s    K   a   r   y   o   t   y   p   e    N   o   r   m   a    l    N   o   r   m   a    l    N   o   r   m   a    l  —    N   o   r   m   a    l    N   o   r   m   a    l  —    S   u    b   t   e    l   o   m   e   r    i   c   s   c   r   e   e   n    i   n   g    N   o   r   m   a    l    F   r   a    X    N   o   r   m   a    l    F   a   m    i    l   y    h    i   s   t   o   r   y    N   e   g   a   t    i   v   e    f   o   r    N    F    1    /    N    S    F   a   t    h   e   r   s   a    i    d   t   o    h   a   v   e    N    F    1    S   o   n   o    f    P   a   t    i   e   n   t    2    M   o   t    h   e   r   o    f    P   a   t    i   e   n   t    5 ,   s    i   s   t   e   r   s   a    i    d   t   o    h   a   v   e    N    F    1    D   a   u   g    h   t   e   r   o    f    P   a   t    i   e   n   t    4    F   a   t    h   e   r   s   a    i    d   t   o    h   a   v   e    N    F    1 ,   m   a   t   e   r   n   a    l   g   r   a   n    d   m   o   t    h   e   r    h   a    d   c   a    f   e    ´  -   a   u  -    l   a    i   t   s   p   o   t   s    N   e   g   a   t    i   v   e    f   o   r    N    F    1    /    N    S    M   u   t   a   t    i   o   n   a    l   s   c   r   e   e   n    i   n   g     N    F     1     L    1    1    9    6    R    (   c .    3    5    8    7    T      >     G ,   e   x   o   n    2    1    )   c .    1    7    5    6_    1    7    5    9    d   e    l    4    (   e   x   o   n    2    1    )   c .    1    7    5    6_    1    7    5    9    d   e    l    4    (   e   x   o   n    2    1    )   c .    3    0    6    0    d   e    l    A    (   e   x   o   n    1    8    )   c .    3    0    6    0    d   e    l    A    (   e   x   o   n    1    8    )   c .    7    9    6_    8    0    3    d   e    l    8    (    G    T    T    T    G    G    C    C ,   e   x   o   n    6    )    W    h   o    l   e   g   e   n   e    d   e    l   e   t    i   o   n     P     T    P    N     1     1     N   o   r   m   a    l    N   o   r   m   a    l    N   o   t   p   e   r    f   o   r   m   e    d    N   o   t   p   e   r    f   o   r   m   e    d    N   o   r   m   a    l    N   o   r   m   a    l    N   o   r   m   a    l     N   o   n   e   o    f   t    h   e   p   a   t    i   e   n   t   s    h   a    d   o   p   t    i   c   g    l    i   o   m   a   o   r   c   r   y   p   t   o   r   c    h    i    d    i   s   m .    *    I   n   v   e   s   t    i   g   a   t    i   o   n   w    i   t    h   s    l    i   t    l   a   m   p   w   a   s   n   o   t   c   o   n    d   u   c   t   e    d    i   n   t    h   e   s   e   p   a   t    i   e   n   t   s .     T    A    B    L    E    I .    (      C   o   n    t    i   n   u   e     d     )    P   a   t    i   e   n   t    1    2    3 ,   s   o   n   o    f    2    4 ,   m   o   t    h   e   r   o    f    5    5    6    7  American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a   diagnosis of LEOPARD syndrome based on thepresence of multiple lentigines, cafe´-au-lait spots,aortic stenosis and mild mental retardation wasshown to harbor a de novo NF1 missense mutation[Wu et al., 1996], but the majority of LEOPARDsyndrome patients harbor mutations in the  PTPN11 gene [Digilio et al., 2002, 2006; Legius et al., 2002;Sarkozy et al., 2004]. Notably, in the LEOPARDsyndromepatientseriesofDigilioetal.[2006],oneof the  PTPN11  mutation negative infants was later onclinically diagnosed as having NF1, because of classical NF1 in the mother. Weanalyzedtwosporadicpatientsandafatherandhis son fitting into the diagnosis of NFNS (Patients 2,3, 6, and 7), a mother and her daughter withneurofibromatosis and Noonan-like features(Patients 4 and 5), and a sporadic patient withclassical NS phenotype in addition to cafe´-au-laitspots, which might qualify him for a diagnosis of either atypical LEOPARD syndrome or atypical WS F IG . 1.  a  ,  b : Patient 2: note pterygium colli, low posterior hair line, hypertelorism, down-slanting palpebral fissures, deep set and posteriorly rotated ears, inferiorpectus excavatum, multiple cafe´-au-lait spots, and neurofibromas. Patient 3 ¼ son of Patient 2 atthe newborn age ( c , d )and at the age of 7 months ( e , f  ) and 20 month( g ): note remarkable development of facial minor anomalies such as hypertelorism, downslanting palpebral fissures, bulbousnasal tip, low set ears, and the two largecafe´-au-lait-spots. h  , i  :Patient6:notehypertelorism,down-slantingpalpebralfissures,highnasalroot,lowsetears,broadforeheadandabundanceofcafe´-au-laitspots,and neurofibromas.  j : Patient 4 ¼ mother of Patient 5: note hypertelorism, bulbous nasal tip, and multiple cafe´-au-lait spots, and neurofibromas.  k  ,  l  : Patient 5: notehypertelorism, downslanting palpebral fissures, epidermal nevus of the neck, postural asymmetry due to scoliosis, pectus excavatum, and clinical signs of theneurofibroma of the tongue: swelling of the tongue and neck-line.  m  : Patient 7: note down-slanting palpebral fissures, hypertelorism, webbed neck, multitude of neurofibromas,onelargefrontalcafe´-au-laitspot, andscar aftersurgicaltreatment ofherscoliosis.[Colorfigure canbeviewedin theonline issue,whichisavailable at] NEUROFIBROMATOSIS NOONAN SYNDROME  2753  American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a 
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