Short-Rib Polydactyly Syndromes

Harold Chen

ContentsSynonyms and Related Disorders . . . . . . . . . . . . . . . . . . . . 1

Genetics/Basic Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Diagnostic Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Genetic Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Short-rib polydactyly syndromes (SRPSs) are aheterogeneous group of recessively inheritedlethal skeletal dysplasia. There are four classicsubtypes: type I (Saldino-Noonan) (SRPS I),type II (Majewski) (SRPS II), type III (Verma-Naumoff) (SRPS III), and type IV (Beemer-Langer) (SRPS IV).

Synonyms and Related Disorders

Lethal short-rib polydactyly syndromes(Martinez-Frias et al. 1993); SRPS I (Saldino-Noonan syndrome, polydactyly with neonatalchondrodystrophy type I); SRPS II (Majewskisyndrome, polydactyly with neonatalchondrodystrophy type II); SRPS III (Verma-Naumoff syndrome, polydactyly with neonatalchondrodystrophy type III); SRPS IV (Beemer-Langer syndrome, short-rib syndrome, Beemertype)

Genetics/Basic Defects

1. Inheritance:1. Autosomal recessive in all four subtypes2. Saldino-Noonan syndrome: affected sibs

(Richardson et al. 1977)3. Majewski syndrome: parental consanguin-

ity (Black et al. 1982; Cooper and Hall1982), affected siblings (Motegi et al.1979)

H. Chen (*)Medical Genetics, Shriners Hospitals for Children,Shreveport, LA, USA

Perinatal and Clinical Genetics, Department of Pediatrics,LSU Health Sciences Center, Shreveport, LA, USAe-mail: hchen@lsuhsc.edu

# Springer Science+Business Media LLC 2016H. Chen (ed.), Atlas of Genetic Diagnosis and Counseling,DOI 10.1007/978-1-4614-6430-3_214-2

1

4. Beemer type: affected sibs (Hennekam1991)

2. Different subtypes of SRPS (Elçioğlu and Hall2002):1. A great overlap of anomalies present

among different subtypes contributing todiagnostic dilemmas in the short-rib poly-dactyly syndrome group

2. Possibly represent a continuous spectrumwith variable expressivity, suggested bysome reports

3. Ciliary abnormalities due to defects in theretrograde transport protein DYNC2H1 inshort-rib polydactyly syndrome (Merrill et al.2009):1. Homozygosity by descent mapping in a

consanguineous SRPS family identified agenomic region that containedDYNC2H1,a cytoplasmic dynein involved in retro-grade transport in the cilium. Affectedindividuals in the family were homozy-gous for an exon 12 missense mutationthat predicted the amino acid substitutionR587C.

2. Compound heterozygosity for one mis-sense and one null mutation were identi-fied in two additional nonconsanguineousSRPS families.

3. Cultured chondrocytes from affected indi-viduals showed morphologically abnor-mal, shortened cilia. In addition, thechondrocytes showed abnormal cytoskel-etal microtubule architecture, implicatingan altered microtubule network as part ofthe disease process.

4. These findings establish SRPS as a ciliadisorder and demonstrate that DYNC2H1is essential for skeletogenesis and growth.

5. Mutations inDYNC2LI1 disrupt cilia func-tion and cause short-rib polydactyly syn-drome (Taylor et al. 2015).

6. Identification of novel DYNC2H1 muta-tions associated with short-rib polydactylysyndrome type III using next-generationpanel sequencing (Chen et al. 2016).

7. DYNC2H1 mutations also cause asphyxi-ating thoracic dystrophy: ATD and SRPtype III are variants of a single disorder

belonging to the ciliopathy group(Dagoneau et al. 2009).

4. NEK1 mutations cause short-rib polydactylysyndrome type Majewski (Thiel et al. 2011).

5. NEK1 and DYNC2H1 are both involved inshort-rib polydactyly Majewski type but notin Beemer Langer cases (Hokayem et al.2012).

6. Short-rib polydactyly syndromes (SRPS) arisefrom mutations in genes involved in retrogradeintraflagellar transport (IFT) and basal bodyhomeostasis, which are critical for cilia assem-bly and function. Recently, mutations inWDR34 orWDR60 (candidate dynein interme-diate chains) were identified in SRPS.Tctex1d2, which associates with Wdr34,Wdr60, and other dynein complex 1 and 2 sub-units, has been identified and characterized(Gholkar et al. 2015). Tctex1d2 and Wdr60localize to the base of the cilium and theirdepletion causes defects in ciliogenesis.IFT52 mutations destabilize anterograde com-plex assembly, disrupt ciliogenesis, and resultin short-rib polydactyly syndrome (Zhang et al.2016).

7. Short-rib polydactyly and Jeune syndromes arecaused by mutations in WDR60 (McInerney-Leo et al. 2013).

8. Mutations in KIAA0586 cause lethalciliopathies ranging from a hydrolethalus phe-notype to short-rib polydactyly syndrome(Alby et al. 2015).

Clinical Features

1. Variable expression of short-rib polydactylysyndrome (Sillence 1980; Sillence et al. 1987)

2. SRPS I (Saldino-Noonan)1. Constant findings:

1. Severely shortened (flipper-like)limbs with postaxial polydactyly

2. Small/narrow thorax with short ribsand hypoplastic lungs

3. Protuberant abdomen4. Early neonatal death

2. Common findings:1. Hydrops fetalis

2 H. Chen

2. Gastrointestinal abnormalities:1. Esophageal atresia2. Short small intestine3. Malrotation of the bowel4. Imperforate anus5. Persistent cloaca6. Imperforate anus7. Pancreatic fibrosis and cysts

3. Cardiac malformations:1. Transposition of the great vessels2. Coarctation of the aorta or hypo-

plastic aortic arch3. Ventricular septal defects4. Double-outlet left ventricle

3. Occasional findings:1. Oligohydramnios2. Renal dysplasia/cystic disease3. Abnormal genitalia:

1. Cryptorchidism2. Hypoplastic penis

4. CNS malformations:1. Cerebellar hypoplasia2. Dandy-Walker malformation

5. Bifid epiglottis6. Bifid tongue7. Cleft upper lip

3. SRPS II (Majewski) (Chen et al. 1980):1. Constant findings:

1. Extremely short limbs with pre-/postaxial polydactyly of the handsand feet

2. Small/narrow chest with short ribs andpulmonary hypoplasia

3. Protuberant abdomen4. Median cleft lip or pseudocleft of the

upper and lower lip or cleft palate5. Epiglottis and larynx hypoplasia6. Short/ovoid tibias with round ends7. Presence of premature ossification

centers8. Early neonatal death

2. Common findings:1. Polyhydramnios2. Hydrops fetalis3. Ocular hypertelorism4. Broad and flat nose5. Low-set ears

6. Ambiguous genitalia7. Renal cystic disease

3. Occasional findings:1. Short small intestine2. Malrotation of the bowel3. Cardiac malformations4. Dysplastic pancreas

4. SRPS III (Verma-Naumoff):1. Constant findings:

1. Severely shortened limbs with postax-ial polydactyly

2. Small/narrow thorax with short ribsand hypoplastic lungs

3. Early neonatal death2. Common findings:

1. Hydrops fetalis2. Short cranial base3. Bulging forehead4. Depressed nasal bridge5. Flat occiput6. Renal cystic dysplasia

3. Occasional findings:1. Congenital heart defects:

1. Ventricular septal defect2. Situs inversus

2. Epiglottic hypoplasia3. Intestinal malrotation4. Cloacal developmental abnormalities

and ambiguous genitalia5. SRPS IV (Beemer-Langer) (Beemer et al.

1983; Beemer 1987; Chen et al. 1994):1. Constant findings:

1. Severely shortened limbs with (Yanget al. 1991; Elçioğlu et al. 1996) orwithout postaxial polydactyly

2. Small/narrow thorax with short ribsand hypoplastic lungs

3. Early neonatal death2. Common findings:

1. Hydrops fetalis2. Macrocephaly with frontal bossing3. Ocular hypertelorism4. Flat nasal bridge5. Cleft lip and palate6. Protuberant abdomen

3. Occasional findings:1. CNS abnormalities:

Short-Rib Polydactyly Syndromes 3

1. Holoprosencephaly/absence ofthe corpus callosum/hydrocephalus

2. Dandy-Walker cyst and/or arach-noid cyst

3. Hypothalamic hamartomas2. Lobulated tongue with hamartomas3. Oral frenula4. Congenital heart defects5. Malrotation of the intestine6. Renal malformations:

1. Renal cystic dysplasia2. Atresia of the ureter with

hydronephrosis and hydroureter7. Omphalocele8. Inguinal hernia

6. SRPS-V (Schmidts 2014):1. SRPS-V was only recently described and

the underlying genetic defect identified intwo consecutively affected pregnancies ofa mother from Maori descent fromNew Zealand.

2. Hydrops, narrow chest, and severely short-ened and bowed long bones displayinglack of ossification, hypoplastic scapulae,and peritoneal calcifications, postaxialpoly-syndactyly, and cleft palate werereported.

3. Extraskeletal findings include bilateralcystic hygroma, hypospadias, mainly glo-merular kidney cysts, and intestinalmalrotation.

4. Acromesomelic hypomineralization andcampomelia distinguish SRPS-V fromSRPS subtypes I–III (Kannu et al. 2007;Mill et al. 2011).

Diagnostic Investigations

1. Radiography:1. SRPS I (Saldino-Noonan):

1. Extreme micromelia with severelydysplastic pointed (or ragged)metaphyses of the long tubular bonesand absence of corticomedullarydemarcation

2. Narrow thorax with short/horizontalribs

3. Deficient ossification in calvarium,vertebrae, pelvis, and bones of thehands and feet

4. Small iliac bones with horizontalacetabula

5. Postaxial polydactyly6. Short tibiae

2. SRPS II (Majewski):1. Extreme micromelia with smooth

rounded metaphyses2. Extremely short horizontal ribs3. Normal pelvis and vertebrae4. Disproportionately shortened ovoid-

shaped tibiae5. Pre- and postaxial polydactyly, syn-

dactyly, and brachydactyly6. Advanced skeletal ossification matu-

ration of the proximal femora andhumeri

3. SRPS III (Verma-Naumoff) (Naumoffet al. 1977):1. Extreme micromelia with severely

dysplastic widened metaphyses(bones of the legs) and clearcorticomedullary demarcation of thelong tubular bones

2. Extremely shortened and horizontalribs

3. Small and malformed vertebral bodies4. Shortened cranial base5. Short iliac bones with horizontal

trident lower margin6. Polydactyly

4. SRPS IV (Beemer-Langer):1. Extreme micromelia with smooth

metaphyseal margins2. Extremely shortened and horizontal

ribs3. Small, poorly ossified vertebrae and

increased intervertebral spaces4. High clavicles and small scapulae5. Small iliac bones6. Bowed radii and ulnae7. Tibiae: well tabulated and longer than

fibulae8. Postaxial polydactyly

4 H. Chen

5. Examination of patients with the “Verma-Naumoff” short-rib polydactyly syndromeshowed many radiologic and pathologicfeatures similar to those of type 1 asphyx-iating thoracic dysplasia (Yang et al.1987).

2. Histopathology/necropsy:1. SRPS I (Saldino-Noonan):

1. Markedly retarded and frequentlyderanged endochondral ossification.A large island of fibrous tissue mayoccupy the center of physeal growthzone. A premature ossification centermay be seen in the epiphyseal restingcartilage.

2. Lungs: hypoplasia which is easilyassessed by abnormally small sizeand low weight.

3. Identify associated multiple congeni-tal anomalies listed in the clinicalfeatures.

2. SRPS II (Majewski):1. Markedly retarded endochondral ossi-

fication. The chondrocytes in thephyseal growth zones are markedlyreduced in number and disorderlyarranged

2. Lungs: hypoplasia as in type I3. Identify associated multiple congeni-

tal anomalies listed in the clinicalfeatures.

3. SRPS III (Verma-Naumoff):1. A “bajonet” deformity of the ribs for

misalignment and overlap of cartilag-inous and bony ends (Corsi et al.2002). This deformity resulted froma “tandem” change in endochondralbone formation, that is, arrestedorthotopic cartilage maturation andetherotopic perichondral cartilage dif-ferentiation and ossification. At thecartilaginous end, cartilage matura-tion and vascular invasion wereabsent. At the bony end, longitudinalbone growth occurred by a perichon-dral ectopic growth plate.

2. Markedly retarded endochondral ossi-fication as in type II.

3. A single patient showed chondrocyticinclusions which are PAS reactive anddiastase resistant (Yang et al. 1980).

4. Lung: hypoplasia as in type I.5. Identify associated multiple congeni-

tal anomalies which are less commonin this type.

4. SRPS IV (Beemer-Langer):1. Physeal growth zones showing a

prominent but disorganized zone ofhypertrophy. The vascular penetrationof physeal cartilage is irregular.

2. Lungs: hypoplasia as in type I3. Identify associated multiple congeni-

tal anomalies listed in the clinicalfeatures.

Genetic Counseling

1. Recurrence risk:1. Patient’s sib: 25 %.2. Patient’s offspring: The patients will not

survive to reproductive age.2. Prenatal diagnosis, not always possible to dif-

ferentiate the subtypes:1. Ultrasonography for SRPS I (Saldino-

Noonan) (Meizner and Bar-Ziv 1989):1. Short fetal limbs2. Narrow thorax3. Polydactyly4. Pointed metaphyses5. Dysplastic cystic kidneys6. Congenital heart defect7. Genital anomalies

2. Ultrasonography for SRPS II (Majewski)(Benacerraf 1993):1. With a positive family history of

Majewski syndrome:1. Presence of short fetal limbs2. Other skeletal findings

2. Without a family history:1. Short fetal limbs2. Disproportionately short tibia3. Very narrow fetal chest4. Short ribs

Short-Rib Polydactyly Syndromes 5

5. Bilateral postaxial polydactyly ofthe hands and feet

6. Median cleft lip and palate7. Polyhydramnios8. Hydrops9. Marked shortened humerus and

femur10. Severe bowing and deformity of

the bones of the lower leg andforearm

11. Hypoplastic lungs12. Congenital heart defect13. Enlarged echogenic kidneys14. Genital anomalies

3. Ultrasonography for SRPS III (Verma-Naumoff) (Meizner and Bar-Ziv 1985;Meizner and Barnhard 1995; Golombecket al. 2001):1. Short fetal limbs2. Small/narrow thorax3. Short thin ribs4. Polydactyly5. Widened metaphyses with marginal

spurs6. Micromelia

4. Ultrasonography for SRPS IV (Beemer-Langer):1. Short fetal bones2. Small/narrow thorax3. Short thin ribs4. Polydactyly

5. Prenatal diagnosis of short-rib polydactylysyndrome type 3 (Verma-Naumoff type)by three-dimensional helical computedtomography (Yamada et al. 2011)

6. Fetoscopy (Toftager-Larsen and Benzie1984):1. To identify fetus with SRPS

phenotype2. An invasive procedure currently

replaced by ultrasonography3. Management:

1. Supportive therapy only for these lethalentities.

2. In cases with SRPS, persistent pulmonaryhypertension of the newborn (PPHN) candevelop dependent on the degree of tho-racic narrowness and pulmonary

hypoplasia and that PPHN can be resistantto therapy (Demir et al. 2015).

References

Alby, C., Piquand, K., Huber, C., et al. (2015).Mutations inKIAA0586 cause lethal ciliopathies ranging from ahydrolethalus phenotype to short-rib polydactyly syn-drome. American Journal of Human Genetics, 97,311–318.

Beemer, F. A. (1987). Short-rib syndrome classification.American Journal of Medical Genetics. Supplement, 3,209–210.

Beemer, F. A., Langer, L. O., Jr., Klep-de Pater, J. M., et al.(1983). A new short rib syndrome: Report of two cases.American Journal of Medical Genetics, 14, 115–123.

Benacerraf, B. R. (1993). Prenatal sonographic diagnosisof short rib-polydactyly syndrome type II, Majewskitype. Journal of Ultrasound in Medicine, 12, 552–555.

Black, I. L., Fitzsimmons, J., Fitzsimmons, E., et al.(1982). Parental consanguinity and the Majewski syn-drome. Journal of Medical Genetics, 19, 141–143.

Chen, H., Yang, S. S., Gonzalez, E., Fowler, M., Al Saadi,A., et al. (1980). Short rib-polydactyly syndrome,Majewski type. American Journal of Medical Genetics,7, 215–222.

Chen, H., Mirkin, D., & Yang, S. (1994). De novo 17qparacentric inversion mosaicism in a patient withBeemer-Langer type short rib-polydactyly syndromewith special consideration to the classification of shortrib polydactyly syndromes. American Journal of Med-ical Genetics, 53, 165–171.

Chen, L. S., Shi, S. J., Zou, P. S., et al. (2016). Identifica-tion of novel DYNC2H1 mutations associated withshort rib-polydactyly syndrome type III using next-generation panel sequencing. Genetics and MolecularResearch, 15, 1–9.

Cooper, C. P., & Hall, C. M. (1982). Lethal short-ribpolydactyly syndrome of the Majewski type: A reportof three cases. Radiology, 144, 513–517.

Corsi, A., Riminucci, M., Roggini, M., et al. (2002). Shortrib polydactyly syndrome type III: Histopathogenesisof the skeletal phenotype. Pediatric and Developmen-tal Pathology, 5, 91–96.

Dagoneau, N., Goulet, M., Geneviève, D., et al. (2009).DYNC2H1 mutations cause asphyxiating thoracic dys-trophy and short rib-polydactyly syndrome, type III.American Journal of Human Genetics, 84, 706–711.

Demir, N., Peker, E., Ece, İ., et al. (2015). A rare cause ofpersistent pulmonary hypertension resistant to therapyin the Newborn: Short-Rib Polydactyly syndrome.Case Reports in Pulmonology, 2015, 1–3.

Elçioğlu, N. H., & Hall, C. M. (2002). Diagnosticdilemmas in the short rib-polydactyly syndrome

6 H. Chen

group. American Journal of Medical Genetics, 111,392–400.

Elçioğlu, N., Karatekin, G., Sezgin, B., et al. (1996). Shortrib-polydactyly syndrome in twins: Beemer-Langertype with polydactyly. Clinical Genetics, 50, 159–163.

Gholkar, A. A., Senese, S., Lo, Y.-C., et al. (2015).Tctex1d2 associates with short-rib polydactyly syn-drome proteins and is required for ciliogenesis. CellCycle, 14, 1116–1125.

Golombeck, K., Jacobs, V. R., von Kaisenberg, C., et al.(2001). Short rib-polydactyly syndrome type III: Com-parison of ultrasound, radiology, and pathology find-ings. Fetal Diagnosis and Therapy, 16, 133–138.

Hennekam, R. C. (1991). Short rib syndrome-Beemer typein sibs. American Journal of Medical Genetics, 40,230–233.

Hokayem, J. E., Huber, C., Couvé, A., et al. (2012). NEK1and DYNC2H1 are both involved in short rib polydac-tyly Majewski type but not in Beemer Langer cases.Journal of Medical Genetics, 49, 227–233.

Kannu, P., McFarlane, J. H., Savarirayan, R., et al. (2007).An unclassifiable short rib-polydactyly syndrome withacromesomelic hypomineralization and campomelia insiblings. American Journal of Medical Genetics A,143A, 2607–2611.

Martinez-Frias, M. L., Bermejo, E., Urioste, M., et al.(1993). Lethal short rib-polydactyly syndromes: Fur-ther evidence for their overlapping in a continuousspectrum. Journal of Medical Genetics, 30, 937–941.

McInerney-Leo, A. M., Schmidts, M., Cortés, C. R., et al.(2013). Short-rib polydactyly and Jeune syndromes arecaused by mutations in WDR60. American Journal ofHuman Genetics, 93, 515–523.

Meizner, I., & Barnhard, Y. (1995). Short-rib polydactylysyndrome (SRPS) type III diagnosed during routineprenatal ultrasonographic screening. A case report.Prenatal Diagnosis, 15, 665–668.

Meizner, I., & Bar-Ziv, J. (1985). Prenatal ultrasonic diag-nosis of short-rib polydactyly syndrome (SRPS) typeIII: A case report and a proposed approach to thediagnosis of SRPS and related conditions. Journal ofClinical Ultrasound, 13, 284–287.

Meizner, I., & Bar-Ziv, J. (1989). Prenatal ultrasonic diag-nosis of short rib polydactyly syndrome, type I. A casereport. The Journal of Reproductive Medicine, 34,668–672.

Merrill, A. E., Merriman, B., Parrington-Rock, C., et al.(2009). Ciliary abnormalities due to defects in the ret-rograde transport protein DYNC2H1 in short-rib poly-dactyly syndrome. American Journal of HumanGenetics, 84, 542–549.

Mill, P., Lockhart, P. J., Fitzpatrick, E., et al. (2011).Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormalciliogenesis. American Journal of Human Genetics,88, 508–515.

Motegi, T., Kusunoki, M., Nishi, T., et al. (1979). Shortrib-polydactyly syndrome, Majewski type, in two malesiblings. Human Genetics, 49, 269–275.

Naumoff, P., Young, L. W., Mazer, J., et al. (1977). Shortrib-polydactyly syndrome type 3. Radiology, 122,443–447.

Richardson, M. M., Beaudet, A. L., Wagner, M. L., et al.(1977). Prenatal diagnosis of recurrence of Saldino-Noonan dwarfism. Journal of Pediatrics, 91, 467–471.

Schmidts, M. (2014). Clinical genetics and pathobiologyof ciliary chondrodysplasias. Pediatric Genetics, 3,46–94.

Sillence, D. O. (1980). Non-Majewski shortrib-polydactyly syndrome. American Journal of Medi-cal Genetics, 7, 223–229.

Sillence, D., Kozlowski, K., Bar-Ziv, J., et al. (1987).Perinatally lethal short rib-polydactyly syndromes.1. Variability in known syndromes. Pediatric Radiol-ogy, 17, 474–480.

Taylor, S. P., Dantas, T. J., Duran, I., et al. (2015). Muta-tions in DYNC2LI1 disrupt cilia function and causeshort rib polydactyly syndrome. Nature Communica-tions, 6, 1–23.

Thiel, C., Kessler, K., Giessl, A., et al. (2011). NEK1mutations cause short-rib polydactyly syndrome typeMajewski. American Journal of Human Genetics, 88,106–114.

Toftager-Larsen, K., & Benzie, R. J. (1984). Fetoscopy inprenatal diagnosis of the Majewski and the Saldino-Noonan types of the Short Rib-Polydactyly syndromes.Clinical Genetics, 26, 56–60.

Yamada, T., Nishimura, G., Nishida, K., et al. (2011).Prenatal diagnosis of short-rib polydactyly syndrometype 3 (Verma-Naumoff type) by three-dimensionalhelical computed tomography. Journal of Obstetricsand Gynaecology Research, 37, 151–155.

Yang, S. S., Lin, C. S., Al Saadi, A., et al. (1980). Shortrib-polydactyly syndrome, type 3 with chondrocyticinclusions: Report of a case and review of the literature.American Journal of Medical Genetics, 7, 205–213.

Yang, S. S., Langer, L. O., Jr., Cacciarelli, A., et al. (1987).Three conditions in neonatal asphyxiating thoracic dys-plasia (Jeune) and short rib-polydactyly syndromespectrum: A clinicopathologic study. American Jour-nal of Medical Genetics. Supplement, 3, 191–207.

Yang, S. S., Roth, J. A., Langer, L. O., et al. (1991). Shortrib syndrome Beemer-Langer type with polydactyly: Amultiple congenital anomalies syndrome. AmericanJournal of Medical Genetics, 39, 243–246.

Zhang, W., Taylor, S. P., Nevarez, L., et al. (2016). IFT52mutations destabilize anterograde complex assembly,disrupt ciliogenesis and result in short rib polydactylysyndrome. Human Molecular Genetics, 27 July 2016.[Epub ahead of print].

Short-Rib Polydactyly Syndromes 7

Fig. 1 (a, b) Radiograph ofa neonate with Saldino-Noonan syndrome (SRPS I)showing extremelyshortened horizontal ribs,very small and dysplasticvertebral bodies and iliaccones, and very shorttubular bones with irregularmetaphyses

Fig. 2 Photomicrograph of femur (SRPS I) shows mark-edly retarded and disorganized physeal growth zone

Fig. 3 Photomicrograph of humerus (SRPS I) showsmarkedly disrupted physeal growth zone by a large carti-lage canal-like vascular fibrous tissue. In addition, there is alarge premature ossification center (upper one third of thepicture)

8 H. Chen

Fig. 4 (a, b) A neonatewith Majewski syndrome(SRPS II) showed hydrops;a large head; hairy forehead;small, malformed, andlow-set ears; telecanthus;short nose; a flat nasalbridge; a central cleft ofupper and lower lips; shortneck; short and narrowchest; markedly distendedabdomen with ascites; andextremely short limbs withpre- and postaxialpolydactyly, syndactyly,and brachydactyly

Fig. 5 Mouth of the neonate in Fig. 4 showing lobulatedtongue and mucosal frenula

Short-Rib Polydactyly Syndromes 9

Fig. 7 (a, b) Hands and feet showed pre- and postaxial polydactyly, syndactyly, and brachydactyly (SRPS II)

Fig. 6 Ambiguous genitalia with a barely visiblemicropenis (SRPS II)

10 H. Chen

Fig. 9 Respiratory system (necropsy) (SRPS II) showinga small larynx with hypoplastic epiglottis (arrow) andremarkably small and hypoplastic lungs. The patient’sthymus is juxtaposed for comparison

Fig. 10 Photomicrograph of tibia cartilage (SRPS II)(Hematoxylin-eosin, �108) showing a markedly stuntedand disorganized physeal growth zone

Fig. 8 (a–c) Radiographs (SRPS II) showing extremelyshort and horizontal ribs, high clavicles, unremarkablespine and pelvis, and premature ossification of the proxi-mal epiphyses of the humeri, femora, and lateral cuboids.

The tubular bones were extremely short, especially themesomelic segments. The tibiae were disproportionatelyshort and oval in shape

Short-Rib Polydactyly Syndromes 11

Fig. 11 Photomicrograph of renal cortex showing manydilated glomeruli and mildly cystic renal tubules (SRPS II)

Fig. 12 (a, b) Radiographsof the skeletal system(SRPS III) showingextremely short andhorizontal ribs, smalldysplastic vertebral bodiesand ilia, and short tubularbones with widenedmetaphyses withlongitudinal spurs

12 H. Chen

Fig. 13 Photomicrograph of the cartilage of the iliac crest(SRPS III) showing retardation and disorganization ofphyseal growth zone

Fig. 14 Higher magnification of the chondrocytes in theresting cartilage and the physeal zone of proliferation fre-quently show cytoplasmic inclusions (PAS after diastasedigestion) (SRPS III)

Short-Rib Polydactyly Syndromes 13

Fig. 15 (a–e) A fetus with Beemer-Langer syndromeshowing macrocephaly, cystic hygroma, severe micro-/retrognathia with cleft palate, low-set and malformedears, short limbs, narrow thorax, protuberant abdomenwith an omphalocele, and polydactyly. The radiographsshow short and horizontal ribs, small scapulae, relatively

poorly ossified vertebral bodies, small ilia, short tubularbones with absence of metaphyseal spicules, bowed radiiand ulnae, and postaxial polydactyly. The ultrasonographyshows porencephalic cyst. The fetus also had a de novoparacentric inversion of chromosome 17q (q12;q25)

14 H. Chen

Fig. 16 Radiograph of another premature neonate (SRPSIV) showing extremely short and horizontal ribs, smalldysplastic vertebral bodies, small iliac wings, and shorttubular bone

Fig. 17 Physeal growth zone of femur showing promi-nent but disorganized zone of hypertrophy (SRPS IV)

Short-Rib Polydactyly Syndromes 15