shprintzen-goldberg syndrome: a clinical analysis
TRANSCRIPT
Shprintzen-Goldberg Syndrome: A Clinical Analysis
Marie T. Greally,1* John C. Carey,2 Dianna M. Milewicz,3 Louanne Hudgins,4 Rosalie B. Goldberg,5Robert J. Shprintzen,5 Anthony J. Cousineau,6 Wilbur L. Smith Jr.,7 G. Frank Judisch,8 andJames W. Hanson9
1Department of Pediatrics, Arabian Gulf University, Manama, Bahrain2Department of Pediatrics, University of Utah Medical Center, Salt Lake City, Utah3University of Texas, Health Science Center at Houston, Houston, Texas4Children’s Hospital and Medical Center, University of Washington School of Medicine, Seattle, Washington5Montefiore Medical Center, Bronx, New York6Department of Pediatrics, Beaumont Clinic, Ltd., Green Bay, Wisconsin7Department of Radiology, University of Iowa, Iowa City, Iowa8Department of Ophthalmology, University of Iowa, Iowa City, Iowa9Department of Pediatrics, University of Iowa, Iowa City, Iowa
Shprintzen-Goldberg syndrome is one of agroup of disorders characterized by cranio-synostosis and marfanoid habitus. Elevencases were reported previously. We present4 new patients and review one of the pa-tients of the original report of Shprintzenand Goldberg [1982: J Craniofac Genet DevBiol 2:65–74], 15 years later. The clinical andradiologic findings on our patients are com-pared with those of the previously reportedpatients and also with those of Furlong et al.[1987: Am J Med Genet 26:599–604] and La-combe and Battin [1993: Clin Dysmorphol 2:220–224], who share many of the character-istics of Shprintzen-Goldberg syndrome.Some of the clinical data are helpful in de-termining if the patients of Furlong et al.[1987: Am J Med Genet 26:599–604] and La-combe and Battin [1993: Clin Dysmorphol 2:220–224] have a separate syndrome or rep-resent a variant of Shprintzen-Goldbergsyndrome. However, radiologic investiga-tions appear to be more specific, since anabnormality of the first and second cervicalvertebrae, hydrocephalus, dilatation of thelateral ventricles, and a Chiari-I malforma-tion of the brain were found only in the pa-tients with Shprintzen-Goldberg syndrome.The apparently diagnostic findings of the 15patients with this syndrome may be helpfulin differentiating between Shprintzen-Goldberg syndrome and other syndromeswith craniosynostosis and marfanoid habi-tus. Am. J. Med. Genet. 76:202–212, 1998.© 1998 Wiley-Liss, Inc.
KEY WORDS: Shprintzen-Goldberg syn-drome; Chiari-I brain mal-formation; C1-C2 abnor-mality; craniosynostosis;marfanoid habitus; mentalretardation; fibrillin-1; trans-forming growth factor beta
INTRODUCTIONThe first patient with the characteristics of what is
now known as Shprintzen-Goldberg syndrome was re-ported by Sugarman and Vogel [1981]. This was a 17-year-old male with plagiocephaly, severe craniofacialand skeletal anomalies, umbilical and inguinal her-niae, hypotonia, and mental retardation. Radiologic in-vestigations showed multiple craniofacial, vertebral,and limb abnormalities.
The following year, Shprintzen and Goldberg [1982]reported similar findings in 2 unrelated males. In ad-dition, both patients had craniosynostosis and obstruc-tive apnea, and one patient had mitral valve prolapse.
In a review of craniosynostosis and related syn-dromes, Cohen [1979] included the patients of Shprint-zen and Goldberg under the term ‘‘Montefiore’’ syn-drome, naming the syndrome after the hospital wherethese patients were diagnosed. The syndrome was sub-sequently reviewed, under its current appellation, asone of a group of disorders with craniosynostosis andmarfanoid habitus [Cohen, 1986], and included the pa-tient reported by Sugarman and Vogel [1981].
Furlong et al. [1987] reported on a male patient withcraniosynostosis and marfanoid habitus. This patienthad some of the craniofacial and skeletal findings ofShprintzen-Goldberg syndrome but also had severecardiovascular disease. He had normal intelligence.
Another male patient with craniosynostosis, cranio-facial and skeletal anomalies, and aortic root dilatationwas reported by Lacombe and Battin [1993]. This pa-tient also had normal intelligence.
*Correspondence to: Marie T. Greally, M.D., M.Sc., Division ofGenetics, Department of Pediatrics, Arabian Gulf University,P.O. Box 26671, Manama, State of Bahrain, Arabian Gulf.
Received 13 June 1997; Accepted 28 July 1997
American Journal of Medical Genetics 76:202–212 (1998)
© 1998 Wiley-Liss, Inc.
In a brief report, Greally et al. [1990] reported on afemale patient with Shprintzen-Goldberg syndrome(SGS), severe cardiovascular disease, and Chiari-Ibrain malformation. Saal et al. [1995], Ades et al.[1995], and Kosztolanyi et al. [1995] reported a total of6 female patients with Shprintzen-Goldberg syndrome.Two further females with SGS were reported by Soodet al. [1996]. In addition to the craniofacial, skeletal,and neurologic findings of this syndrome, the patient ofSaal et al. [1995] had cloverleaf skull, hydrocephalus,and a Chiari-I brain malformation. Ades et al. [1995]reported on one sporadic case and 3 sisters, two ofwhom were monozygotic (MZ) twins. The skeletal find-ings in all 4 patients included bowing of one or morelong bones. The patient of Kosztolanyi et al. [1995] hadsimilar findings to the patients reported by Shprintzenand Goldberg [1982]. In addition, she had a pericentricinversion of one homologue of chromosome 10. Her phe-notypically normal mother and maternal aunt had asimilar inversion, so the relationship of these findingsto SGS is unclear. The patients of Sood et al. [1996] hadthe craniofacial and other defects of Shprintzen-Goldberg syndrome but also had the typical defects ofMarfan syndrome. One patient had ectopia lentis.
We present 5 patients with Shprintzen-Goldbergsyndrome, 2 females and 3 males. Patient 1 was thesubject of a brief report by Greally et al. [1990]. Patient3 is one of the patients of the original report of Shprint-zen and Goldberg [1982]. His inclusion demonstratesthe natural history of the syndrome in a severely af-fected patient.
Detailed radiologic investigations, and collagen andfibrillin studies, were carried out on patient 1. Fibrillinstudies were also performed on patients 3–5. The clini-cal and radiologic findings on our patients are com-pared with those of the patients in the previously men-tioned reports, and the diagnostic criteria for Shprint-zen-Goldberg syndrome are discussed.
CLINICAL REPORTSPatient 1
B.M. was born to a GI 18-year-old Caucasian motherand a nonconsanguineous 18-year-old Caucasian fa-ther. Pregnancy was uncomplicated and there was noknown exposure to teratogens. Delivery at term was bycesarean section for cephalopelvic disproportion. Birthweight was 4,090 g (>90th centile) and length was 53cm (>90th centile). Large head size, hypotonia, umbili-cal hernia, and deformities of the feet and legs werenoted at birth.
At age 7 months, surgical correction of bilateral met-arsus adductus and genu recurvatum was initiated.EMI studies, carried out at this age because of a tenseand bulging anterior fontanelle, indicated possible bi-lateral frontal ‘‘atrophy.’’ A reducible lumbar kyphosiswas confirmed radiologically. Chromosomes were ap-parently normal (46,XX). A skull radiograph at 11months showed dolichocephaly and premature closureof the metopic suture. At 7 1/2 years a CT scan showedmoderate enlargement of the lateral ventricles and
mild enlargement of the third ventricle. Muscle biopsy,serum CPK, EMG, motor nerve conduction velocity,and metabolic screening studies were carried out at 1year, and all results were normal.
Surgical procedures included umbilical hernia repairat 23 months, myringotomy tube placement at 7 years,and partial adenoidectomy at 10 years.
B.M. has a mild conductive hearing loss and has beenhospitalized for investigation of headache and also forsevere anorexia.
At age 12 years B.M. was a small, thin, prepubertalgirl. Her height was 140 cm (5th centile) and weight 26kg (<3rd centile). Skull shape was dolichocephalic, witha deep indentation over the coronal suture. Scalp hairwas fine and sparse. The forehead was high and promi-nent, with a high anterior hairline. Shallow orbits withocular proptosis, telecanthus, hypertelorism, and widedownslanting palebral fissures were noted. Inner can-thal distance measured 3.5 cm (+2 SD), outer canthaldistance was 12.0 cm (>97th centile), and interpupil-lary distance was 6.2 cm (97th centile). The ears werestructurally normal but were apparently low-set andposteriorly angulated. Maxillary hypoplasia, microgna-thia, a high narrow palate with prominent palatalridges (Fig. 1), and a bifid uvula were also noted. Therewas severe dental malocclusion, with enamel defects onpremolars and molars bilaterally (Fig. 2).
She also had severe pectus excavatum and mild tho-racolumbar scoliosis. The hands were long and thinwith arachnodactyly but no camptodactyly. The feetwere long and thin with long toes, severe pes planus,and bilateral reducible metatarsus adductus. All jointswere hyperextensible with the exception of the rightelbow joint, which showed dislocation of the radialhead. The knees showed genu recurvatum and sub-luxation of the left patella.
Body proportions were normal, with an upper:lowersegment ratio of 1.
B.M. has moderate psychomotor delay. She was
Fig. 1. Patient 1. High palate with prominent lateral palatine ridgesand dental malpositioning.
Shprintzen-Goldberg Syndrome 203
standing independently at 18 months and walked at 20months. The Wecshler Intelligence Scale for Children-Revised (WISC-R) was administered at age 7 1/2. Herverbal IQ score was 80, performance IQ score was 74,and full-scale IQ was 76. She attends regular schooland is in an age-appropriate grade with some specialeducation classes each day. She is a very pleasant andaffectionate young girl who is popular with her class-mates. Family history identified a maternal brotherand uncle who are described as ‘‘slow.’’ Both requiredspecial education classes in school. The mother has ahistory of mild hypotonia and joint laxity. Both parentsare high-school graduates with no history of learningdifficulties. B.M. has 2 healthy maternal half-siblingsand no known relatives with a similar disorder.
Investigations
A two-dimensional (2-D) echocardiogram demon-strated enlargement of the aortic root and mitral valveprolapse, with mild mitral insufficiency.
Ophthalmologic examination noted a history of in-termittent exotropia. Visual acuity was 20/20 OD and20/15 OS. Extraocular muscle testing demonstratedexophoria; keratometry readings showed flatter valuesthan normal, and small skip areas of lens rim irregu-larity were seen, especially OD. Ectopia lentis was notseen. Radiologic examination of the skull demonstrateddolichocephaly, hypoplastic mandible with abnormalramus, hypoplastic midface, and ‘‘beaten silver’’ ap-pearance of the skull bones (Fig. 3). Examination of thespine disclosed a C1-C2 fusion abnormality, with a longodontoid process and incorporation or hypoplasia of theanterior arch of C1 (Fig. 4).
In the thoracic region, T9-T10 fusion was noted,while the lumbar area showed mild kyphoscoliosis. Inaddition, the vertebral bodies had a square or box-likeappearance. A chest film showed severe pectus excava-tum.
Magnetic resonance imaging of the brain and brainstem documented mild hydrocephalus (Fig. 5), a Chi-ari-I malformation (Fig. 6), skull deformity, and a longnarrow odontoid process. The lateral ventricles showedasymmetric enlargement of the anterior horns, andthere was minimal deformation of the subarachnoid
space at the level of the craniovertebral junction with-out evidence of cord syrinx.
MRI findings of the abdomen, and ultrasound char-acteristics of the kidneys, were also normal.
Results of collagen studies were normal. Investiga-tion of fibrillin showed normal synthesis and secretionof the protein, but with increased deposition in the ex-tracellular matrix. Chromosomes were normal (46,XX).
Patient 2
A.M. was the product of a term gestation born to a G121-year-old Hispanic mother and a 35-year-old noncon-
Fig. 4. Patient 1. C1-C2 fusion abnormality, with long odontoid processand incorporation/hypoplasia of the anterior arch of C1. Abnormal ramusof mandible.
Fig. 2. Patient 1. Note pitting of dental enamel on upper premolars.
Fig. 3. Patient 1. Dolichocephaly, hypoplastic mandible with unusualangulation of ramus, hypoplastic midface, and ‘‘beaten-silver’’ skull.
204 Greally et al.
sanguineous Hispanic father. Prenatal care was notinitiated until the end of pregnancy. There was no his-tory of medication or teratogen exposures or of polyhy-dramnios. Delivery was spontaneous, with vertex pre-sentation. Birth weight was 3,000 g (25–50th centile),and length was 48.5 cm (50–75th centile). Neonatalprogress was uneventful.
At 3 months, A.M. started to spit up continuously butwas not investigated. At 6 months, he was investigatedbecause of slow motor development. Chromosomeswere normal (46,XY). Skeletal survey demonstratedlong, thin bones consistent with congenital contrac-tural arachnodactyly, which was considered a possiblediagnosis at this time. There was decreased facial ex-pression, giving him a myopathic facial appearance. Hehad considerable micrognathia. His ears showed pos-terior angulation but no crumpling of the helix.
Examination of the chest showed a marked pectusexcavatum (Fig. 7). There was decreased muscle massand subcutaneous tissue throughout the body. He hada very long, thin appearance with lax joints, except forthe feet. His whole-hand measurement was 10.2 cm(which is at the mean), while the third finger was 5 cm,which is above the 97th centile. Palmar and fingercreases were normal. At that time he had no evidenceof scoliosis and had no joint contractures except for hisfeet (Fig. 8).
At 33 months, his head circumference was 48.2 cm
(10th centile), his height was 94 cm (>50th centile), andhis weight was 10.8 kg (<3rd centile).
On physical examination at 10 years, A.M. weighed20 kg (<5th centile) and was 137 cm tall (25–50th cen-tile). He was noted to have developed scoliosis, and hishands showed contractures of the proximal interpha-langeal joints with mild limitation of full extension ofthe fourth and fifth digits (Fig. 9). In addition to thepreviously documented craniofacial anomalies, ocularproptosis, exotropia, a narrow maxilla, and very nar-row palate were also noted.
Craniosynostosis has never been documented in thispatient, but he does have dolichocephaly. An echocar-diogram was performed during hospitalization at age10 years and showed normal cardiac architecture. Oph-thalmologic findings were normal, with no evidence ofectopia lentis. Serum carnitine and lactate levels andurinary organic acids were normal.
A.M. shows significant developmental delay. He didnot walk until after age 5 years. Speech evaluation atage 6 years indicated that his overall language skillswere at the 12-month level. A recent evaluation at age11 8/12 years demonstrated that A.M. has gross motorskills at the 26-month level and fine motor skills at the28-month level. Communication skills were much im-proved, although expressive language is still more de-layed than receptive. Hypotonia continues to be a prob-lem, but A.M. shows significant improvement in self-care and interactive behavior. Family history isnoncontributory.
Patient 3
D.O. (Fig. 10) is patient 2 of the original report ofShprintzen and Goldberg [1982]. Since that publica-tion, he has had a bleeding gastric ulcer with peritoni-tis at age 5 10/12 years. This was followed by additional
Fig. 5. Patient 1. Mild hydrocephalus on T-2-weighted scan.
Fig. 6. Patient 1. Skull deformity, narrow long odontoid, Chiari-I mal-formation: tonsils extend below the foramen magnum.
Shprintzen-Goldberg Syndrome 205
surgery to remove a portion of gangrenous small bowel.Postoperatively he developed pneumonia.
Radiologic examination of the cervical spine at age 5years demonstrated profound subluxation of C1 on C2,with a gap >5 mm between the anterior arch of C1 andthe ossific dens. Subsequent investigation of upper-limb weakness and numbness demonstrated impinge-ment of the odontoid process on the cervical cord.Symptoms were relieved by removal of a portion of theodontoid process. A large umbilical hernia was re-paired at age 8 9/12.
Current physical findings include scoliosis, thoracickyphosis, and flexion contractures of the finger, shoul-der, hip, knee, and ankle joints. He has a deep pectusexcavatum. A skeletal survey showed gracile ribs with
demineralization and undertubulation of all bones. Anophthalmic examination showed myopia but no ectopialentis.
D.O. continues to show significant developmental de-lay and mild retardation. He has multiple joint contrac-tures and is unable to walk without support. Hisspeech is limited. His orthopedic problems have wors-ened significantly in the past 10 years. He has frequentbouts of pneumonia requiring hospitalization. Follow-ing tracheostomy decannulation, D.O. developed sleepapnea.
Patient 4
S.F. is a white male who was born at term to a 21-year-old gravida 1 mother and her 25-year-old noncon-
Fig. 9. Patient 2. Arachnodactyly; contractures of proximal interpha-langeal joints.
Fig. 7. Patient 2. Pectus excavatum.
Fig. 8. Patient 2. Camptodactyly of toes.
206 Greally et al.
sanguineous partner. Pregnancy was complicated byan abnormal glucose tolerance test, which responded todietary treatment. Other teratogenic exposures weredenied. Birth weight was 3,068 g (25–50th centile) andlength 48 cm (50–75th centile). Head circumference(OFC) was 36.8 cm (>90th centile). At birth the patientwas noted to have contractures of the proximal inter-phalangeal joints bilaterally and a left clubfoot. Theelbows could not be fully extended. Cryptorchidism wasalso noted.
S.F. was evaluated in the Medical Genetics Clinic atage 1 month. At that time it was thought that his clini-cal findings were consistent with a diagnosis of distalarthogryposis. Because neither parent had any signs ofthis disorder, it was postulated that the patient repre-sented a new mutation.
When S.F. was reevaluated at age 2 years, his cra-nial configuration had changed. He now had dolicho-cephaly and a rather long, narrow face and exorbitism.There was also the appearance of hypertelorism, mildmicrognathia, and a high, narrow palate. The flexioncontractures of the fingers were improving. His lengthwas between 75–90th centile, his weight was betweenthe 25–50th centile, and his OFC was close to the 98thcentile. A skeletal survey was performed to rule outotopalatodigital syndrome. None of the characteristicfindings of this syndrome were seen. However, skeletalfindings included pectus excavatum, dolichostenome-lia, and craniosynostosis. CT showed mild ventricular
prominence. An ophthalmologic examination showedstrabismus but no myopia or ectopia lentis.
Physical examination showed hypotonia, cryptor-chidism, a right inguinal hernia, ocular hypertelorism,proptosis, strabismus, downslanting palpebral fis-sures, maxillary hypoplasia, a high, narrow palatalarch, micrognathia, and apparently low-set ears.
S.F. attained head control at 4–5 months and walkedunassisted at 20 months. Language development wasdescribed as normal. The patient is considered to beperforming at an age-appropriate level at this time.
Thus, S.F. has always been tall for his age with aheight between the 75–90th centile, but weight hasbeen between the 25–50th centile, and his head sizehas been large (95–98th centile). He has hypotonia andjoint contractures but no cognitive dysfunction. Familyhistory is noncontributory.
Patient 5
K.F. (Fig. 11) is a white female born to a 20-year-oldG3 P2 Ab1 mother and a 23-year-old nonconsanguine-ous father. The mother smoked approximately half apack of cigarettes per day during pregnancy. Birth, atterm, was spontaneous. Birth weight was 3,714 g (75–90th centile) and length 53.6 cm (>90th centile). A pec-tus deformity was noted at birth. During the first 6months of life K.F. had feeding difficulties and washypotonic.
Past medical history includes a diagnosis of high-grade myopia and strabismus at age 4 years. There wasno evidence of ectopia lentis.
A sensorineural hearing defect was diagnosed at 5Fig. 10. Patient 3. Note ocular proptosis, malar hypoplasia, microgna-
thia, and apparently low-set posteriorly angulated auricles.
Fig. 11. Patient 5. Prominence of eyes; facial appearance of a mildlyaffected patient with mild MR.
Shprintzen-Goldberg Syndrome 207
years, and the patient wears a hearing aid. Inguinalherniae were repaired at age 5 years. MRI studies ofthe head at 5 years demonstrated a small pituitarygland. Serum thyroxine, TSH, and cortisol levels werenormal, but growth hormone was less than 1 ng/ml(normal range, 0–10 ng/ml). An echocardiogram wasperformed at age 6 years and demonstrated mitralvalve prolapse without regurgitation and a normal as-cending aorta. Radiologic findings of legs and kneesand bone age were normal.
K.F. rolled over at 4 months and walked at 12months. She did not speak words until 2 1/2 years anddid not speak in complete sentences until much later.She currently attends special classes in school.
Chromosomes (including fragile-X studies) were nor-mal. A diagnosis of homocystinuria was excluded.
On physical examination at age 7 years, K.F. was athin girl with a height of 127.2 cm (95th centile) andweight of 21.8 kg (50th centile). The craniofacial find-ings included ocular proptosis, mild hypertelorism,mild micrognathia, a high palatal arch without tenting,and apparently low-set, posteriorly rotated, and pro-truding ears. She also had a mild pectus deformitywithout scoliosis, normal cardiovascular and abdomi-nal findings, dolichostenomelia, and an upper-to-lowersegment ratio of 57–70.5 cm. In addition she had arach-nodactyly with a hand length of 15 cm (>97th centile)and middle finger length of 6.25 cm (97th centile). Shehad joint hyperextensibility, which was particularlynotable in the ankle joints. Family history is noncon-tributory.
DISCUSSIONThe phenotype of patients with Shprintzen-Goldberg
syndrome includes craniofacial, skeletal, and otheranomalies [Shprintzen and Goldberg, 1982; Sugarmanand Vogel, 1981; Saal et al., 1995; Ades et al., 1995;Kosztolanyi et al., 1995; Sood et al., 1996]. In TablesI–IV the clinical and radiologic findings on 4 new pa-tients with SGS and the interim findings on patient 2of the original report of Shprintzen and Goldberg[1982] are compared with those of 10 reported cases ofSGS and the patients reported by Furlong et al. [1987]and Lacombe and Battin [1993]. Analysis of the datasuggests diagnostic criteria for SGS which appear todistinguish this syndrome from the patients of Furlonget al. [1987] and Lacombe and Battin [1993] and fromother syndromes with craniosynostosis and marfanoidhabitus [Cohen, 1988].
The sex ratio of reported cases of SGS is currently 10F:5 M. It is apparent from Table I that most patientsbegin life as well-nourished babies of greater than av-erage length. The most frequently described craniofa-cial features of all patients include dolichocephaly, ahigh, prominent forehead, ocular proptosis, hypertelor-ism, telecanthus, downslanting palpebral fissures,strabismus, maxillary hypoplasia, high, narrow palatewith prominent lateral palatine ridges, micrognathia,and apparently low-set ears.
The main skeletal findings on patients with Shprint-zen-Goldberg syndrome and the patients reported byFurlong et al. [1987] and Lacombe and Battin [1993]include arachnodactyly, camptodactyly, pes planus, a
pectus deformity, scoliosis, and joint hypermobility(Table II). Talipes equinovarius, metatarsus adductus,and genu recurvatum were recorded only in patientswith SGS.
Aortic root dilatation and mitral valve prolapse werefound in one of our patients (patient 1) and in 2 previ-ously reported cases of SGS ([Ades et al., 1995; Sood etal., 1996]. Mitral valve prolapse was reported in one ofthe original patients of Shprintzen and Goldberg [1982]and was also found in patient 5 of this study. Hypoto-nia, developmental delay, mental retardation, minimalsubcutaneous fat, and cryptorchidism are characteris-tics of patients with SGS, whereas abdominal wall de-fects and myopia are common to all patients (Table III).Ectopia lentis was found in one patient with SGS [Soodet al., 1996].
Radiologic findings are documented in Table IV. Pa-tient 1 of this report demonstrated hydrocephalus, di-latation of the lateral ventricles, Arnold-Chiari-I brainmalformation, a C1-C2 abnormality, square-shapedvertebral bodies, and osteopenia, in addition to cranio-facial abnormalities. Dilatation of the lateral ventricleswas also found in our patient 4, and an abnormality ofC1-C2, thin ribs, and osteopenia in patient 3. Bowing ofribs and long bones [Ades et al., 1995], and supernu-merary ribs and hypoplastic clavicles, were demon-strated in the patients of Ades et al. [1995] and Kostz-tolanyi et al. [1995], but were not found in the patientsof this study.
Patients with Shprintzen-Goldberg syndrome andthe patients of Furlong et al. [1987] and Lacombe andBattin [1993] cannot be separated on the basis of cra-niofacial anomalies (Table I). Skeletal findings are alsovery similar, with the exception of foot deformitieswhich occurred only in SGS patients (Table II). Severecardiovascular disease has now been found in 3 pa-tients with SGS (Table III), so this is no longer a dis-tinguishing trait of the patients of Furlong et al. [1987]and Lacombe and Battin [1993]. The characteristicswhich appear to differentiate between SGS patientsand a possible separate syndrome in the patients ofFurlong et al. [1987] and Lacombe and Battin [1993]may also be the diagnostic defects of Shprintzen-Goldberg syndrome. These include hypotonia, develop-mental delay, mental retardation, cryptorchidism, footdeformities, hydrocephalus, ventriculomegaly, Chiari-Imalformation, and an abnormality of the first and sec-ond cervical vertebrae, in a patient with the previouslydescribed craniofacial and skeletal anomalies. How-ever, with so few reported cases of SGS, it is impossibleto rule out a spectrum of clinical and radiologic findingsin this syndrome which may yet include the patients ofFurlong et al. [1987] and Lacombe and Battin [1993].
Shprintzen-Goldberg syndrome is characterized bycraniostenosis and marfanoid habitus [Cohen, 1988].Other syndromes in this category include Idaho syn-drome II and Antley-Bixler syndrome. Idaho syndromeII [Cohen, 1979] may be distinguished from SGS by lesssevere craniofacial involvement, complete anterior dis-placement of the tibiae, and absent patellae. Antley-Bixler syndrome [Antley and Bixler, 1975; Esobar etal., 1986] is an autosomal-recessive disorder with cra-
208 Greally et al.
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Ocu
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−+
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++
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Pto
sis
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−+
−−
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−−
−−
−−
++
Hyp
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++
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++
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Pro
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++
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Cle
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Sm
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Pec
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Pec
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Sex
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niofacial characteristics, radiohumeral synostosis,femoral and ulnar bowing, and femoral fractures. Theclinical phenotype is clearly distinguishable from thatof SGS.
Since Shprintzen-Goldberg syndrome shares manyof the clinical abnormalities of Marfan syndrome(MFS), an autosomal-dominant disorder caused by mu-tations in the fibrillin-1 (FBN1) gene [Milewicz et al.,1992], analysis of FBN1 was carried out on 4 of ourpatients. This study is in progress and the results willbe presented in a separate report. Fibrillin protein ex-pression studies were normal in patient 1 of the reportof Ades et al. [1995]. In their investigation of 2 patientswith SGS, Sood et al. [1996] found defects in FBN1which included a de novo mutation at codon 1223(C1223Y) in patient 1 and a mutation at codon 1148(P1148A) in patient 2. The mutation in patient 1, whohas ectopia lentis and aortic dilatation, was previouslyreported in a patient with sporadic MFS [Hewett et al.,1994]. In the second patient, the pathogenicity of themutation is unclear, as it has been found in many clini-cal settings, particularly in apparently unaffected rela-tives of MFS patients where its documented frequencywas higher than that of controls. Sood et al. [1996]proposed that this mutation (P1148A) ‘‘defines a pre-disposing allele that is subject to extreme modificationby epistatic, stochastic and/or environmental modifi-ers’’ which may require an additional mutation inFBN1 or at another locus to achieve expression of thephenotype of SGS.
Fibrillin-1 is a major component of the microfibrils ofthe ciliary zonules, and a defect in this protein is asso-ciated with lens subluxation in approximately 60% ofpatients with MFS [Gray and Davies, 1996]. Amongthe 15 reported cases of SGS, only one patient has ec-topia lentis. This observation suggests that a defect infibrillin-1 may not be the main causal basis of SGS.Putnam et al. [1996] proposed that a disruption of anormal interaction between fibrillin-1 and transform-ing growth factor b1 (TGF-b1) during fetal develop-ment could result in neonatal or severe MFS. In SGS,since ectopia lentis is rare, a defect in the TGF-b1 geneitself or in its proposed interaction with fibrillin-1 maybe responsible for the phenotype of this syndrome.
Shprintzen-Goldberg syndrome has been reported asa sporadic occurrence in all cases except in the family ofAdes et al. [1995], where 3 sisters were affected. Thispattern suggests autosomal-recessive inheritance.However, if the proposal of Sood et al. [1996] is correct,and SGS and MFS are caused by allelic mutations,
then it is possible that each sporadic case represents anew dominant mutation and that the family of Ades etal. [1995] represents either heterogeneity for this dis-order or parental germline mosaicism.
REFERENCESAdes LC, Morris LL, Power RG, Wilson M, Haan EA, Bateman JF,
Milewicz DM, Sillence DO (1995): Distinct skeletal abnormalities infour girls with Shprintzen-Goldberg syndrome. Am J Med Genet 57:565–572.
Antley RM, Bixler D (1975): Trapezoidcephaly, midfacial hypoplasia andcartilage abnormalities with multiple synostoses and skeletal frac-tures. In Bergsma D (ed): ‘‘Malformation Syndromes.’’ Amsterdam: Ex-cerpta Medica, for the National Foundation—March of Dimes. BD:OASXI (2):397–401.
Cohen MM Jr (1979): Craniosynostosis and syndromes with craniosynos-tosis: Incidence, genetics, penetrance, variability and new syndromeupdating. In O’Donnell JJ, Hall BD (eds): ‘‘Penetrance and Variabilityin Malformation Syndromes.’’ New York: Alan R. Liss, Inc., for theNational Foundation—March of Dimes. BD:OAS XV (5B):13–63.
Cohen MM Jr (1986): ‘‘Craniosynostosis: Diagnosis, Evaluation and Man-agement.’’ New York: Raven Press.
Cohen MM Jr (1988): Craniosynostosis update 1987. Am J Med Genet[Suppl] 4:99–148.
Escobar LF, Bixler D, Sadone M, Bull MJ (1986): Antley-Bixler syndromefrom a prognostic perspective: Report of a case and review of the lit-erature. Am J Med Genet 29:829–836.
Furlong J, Kurczynski TW, Hennessy JR (1987): New marfanoid syndromewith craniosynostosis. Am J Med Genet 26:599–604.
Gray JR, Davies SJ (1996): Marfan syndrome. J Med Genet 33:403–408.Greally MT, Cousineau A, McGookey D, Byers P, Shprintzen RJ, Goldberg
RB, Hanson JW (1990): Shprintzen-Goldberg syndrome: Further delin-eation of phenotype and investigation for molecular defect. Am J HumGenet [Suppl] 47:58.
Kosztolanyi G, Weisenbach J, Mehes K (1995): Syndrome of arachnodac-tyly, disturbance of cranial ossification, protruding eyes, feeding diffi-culties, and mental retardation. Am J Med Genet 58:213–216.
Lacombe D, Battin J (1993): Marfanoid features and craniosynostosis: Re-port of one case and review. Clin Dysmorphol 2:220–224.
Milewicz DM, Pyeritz RE, Crawford ES, Byers PH (1992): Marfan syn-drome: Defective synthesis, secretion and extracellular matrix forma-tion of fibrillin by cultured dermal fibroblasts. J Clin Invest 89:79–86.
Putnam EA, Cho M, Zinn AB, Towbin JA, Byers PH, Milewicz DM (1996):Delineation of the Marfan phenotype associated with mutations in ex-ons 23–32 of the FBNI gene. Am J Med Genet 62:233–242.
Saal HM, Bulas DI, Allen JF, Vezina LG, Walton D, Rosenbaum KN(1995): Patient with craniosynostosis and marfanoid phenotype(Shprintzen-Goldberg syndrome) and cloverleaf skull. Am J Med Genet57:573–578.
Shprintzen RJ, Goldberg RB (1982): A recurrent pattern syndrome of cra-niosynostosis associated with arachnodactyly and abdominal hernias. JCraniofac Genet Dev Biol 2:65–74.
Sood S, Eldadah ZA, Krause WL, McIntosh I, Dietz HC (1996): Mutation infibrillin-1 and the marfanoid-craniosynostosis (Shprintzen-Goldberg)syndrome. Nat Genet 12:209–211.
Sugarman G, Vogel MW (1981): Case report 76: Craniofacial and muscu-loskeletal abnormalities—A questionable connective tissue disease.Synd Ident 7:16–17.
212 Greally et al.