Short Rib Polydactyly Syndromes

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884 Short rib-polydactyly syndromes (SRPS) are a heterogeneous group of recessively inherited lethal skeletal dysplasia. There are four classic subtypes: type I (Saldino-Noonan) (SRPS I), type II (Majewski) (SRPS II), type III (Verma-Naumoff) (SRPS III), and type IV (Beemer-Langer) (SRPS IV).

GENETICS/BASIC DEFECTS

1. Inheritance: autosomal recessive in all four subtypes 2. Different subtypes of SRPS

a. A great overlap of anomalies present among different subtypes contributing to diagnostic dilemmas in the short rib-polydactyly syndrome group

b. Possibly represent a continuous spectrum with vari- able expressivity, suggested by some reports

CLINICAL FEATURES

1. SRPS I (Saldino-Noonan) a. Constant findings

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

ii. Small/narrow thorax with short ribs and hypoplastic lungs

iii. Protuberant abdomen iv. Early neonatal death b. Common findings

i. Hydrops fetalis

ii. Gastrointestinal abnormalities a) Esophageal atresia b) Short small intestine c) Malrotation of the bowel d) Imperforate anus e) Persistent cloaca f) Imperforate anus

g) Pancreatic fibrosis and cysts iii. Cardiac malformations

a) Transposition of the great vessels

b) Coarctation of the aorta or hypoplastic aortic arch

c) Ventricular septal defects d) Double-outlet left ventricle c. Occasional findings

i. Oligohydramnios

ii. Renal dysplasia/cystic disease iii. Abnormal genitalia

a) Cryptorchidism b) Hypoplastic penis iv. CNS malformations

a) Cerebellar hypoplasia b) Dandy-Walker malformation

v. Bifid epiglottis vi. Bifid tongue vii. Cleft upper lip 2. SRPS II (Majewski)

a. Constant findings

i. Extremely short limbs with pre/postaxial polydactyly of the hands and feet

ii. Small/narrow chest with short ribs and pulmonary hypoplasia

iii. Protuberant abdomen

iv. Median cleft lip or pseudo-cleft of the upper and lower lip or cleft palate

v. Epiglottis and larynx hypoplasia vi. Short/ovoid tibias with round ends vii. Presence of premature ossification centers viii. Early neonatal death

b. Common findings i. Polyhydramnios ii. Hydrops fetalis iii. Ocular hypertelorism

iv. Broad and flat nose v. Low-set ears vi. Ambiguous genitalia vii. Renal cystic disease c. Occasional findings

i. Short small intestine ii. Malrotation of the bowel iii. Cardiac malformations

iv. Dysplastic pancreas 3. SRPS III (Verma-Naumoff)

a. Constant findings

i. Severely shortened limbs with postaxial polydactyly

iii. Early neonatal death b. Common findings

i. Hydrops fetalis ii. Short cranial base iii. Bulging forehead

iv. Depressed nasal bridge v. Flat occiput

vi. Renal cystic dysplasia c. Occasional findings

i. Congenital heart defects a) Ventricular septal defect b) Situs inversus

ii. Epiglottic hypoplasia iii. Intestinal malrotation

iv. Cloacal developmental abnormalities and ambiguous genitalia

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4. SRPS IV (Beemer-Langer) a. Constant findings

i. Severely shortened limbs with or without postaxial polydactyly

iii. Early neonatal death b. Common findings

i. Hydrops fetalis

ii. Macrocephaly with frontal bossing iii. Ocular hypertelorism

iv. Flat nasal bridge v. Cleft lip and palate vi. Protuberant abdomen c. Occasional findings

i. CNS abnormalities

a) Holoprosencephaly/absence of the corpus callosum/hydrocephalus

b) Dandy-Walker cyst and/or arachnoid cyst c) Hypothalamic hamartomas

ii. Lobulated tongue with hamartomas iii. Oral frenula

iv. Congenital heart defects v. Malrotation of the intestine vi. Renal malformations

a) Renal cystic dysplasia

b) Atresia of the ureter with hydronephrosis and hydroureter

vii. Omphalocele viii. Inguinal hernia

DIAGNOSTIC INVESTIGATIONS

1. Radiography

a. SRPS I (Saldino-Noonan)

i. Extreme micromelia with severely dysplastic pointed (or ragged) metaphyses of the long tubular bones, and absence of corticomedullary demarcation

ii. Narrow thorax with short/horizontal ribs iii. Deficient ossification in calvarium, vertebrae,

pelvis, and bones of the hands and feet iv. Small iliac bones with horizontal acetabulae

v. Postaxial polydactyly vi. Short tibiae

b. SRPS II (Majewski)

i. Extreme micromelia with smooth rounded metaphyses

ii. Extremely short horizontal ribs iii. Normal pelvis and vertebrae

iv. Disproportionately shortened ovoid-shaped tibiae v. Pre- and post-axial polydactyly, syndactyly, and

brachydactyly

vi. Advanced skeletal ossification—advanced matu- ration of the proximal femora and humeri c. SRPS III (Verma-Naumoff)

i. Extreme micromelia with severely dysplastic widened metaphyses (bones of the legs) and clear corticomedullary demarcation of the long tubular bones

ii. Extremely shortened and horizontal ribs iii. Small and malformed vertebral bodies

iv. Shortened cranial base

v. Short iliac bones with horizontal trident lower margin

vi. Polydactyly

d. SRPS IV (Beemer-Langer)

i. Extreme micromelia with smooth metaphyseal margins

ii. Extremely shortened and horizontal ribs iii. Small, poorly ossified vertebrae and increased

intervertebral spaces

iv. High clavicles and small scapulae v. Small iliac bones

vi. Bowed radii and ulnae

vii. Tibiae: well tabulated and longer than fibulae viii. Postaxial polydactyly

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

i. Markedly retarded and frequently deranged endochondral ossification. A large island of fibrous tissue may occupy the center of physeal growth zone. A premature ossification center may be seen in the epiphyseal resting cartilage.

ii. Lungs: hypoplasia which is easily assessed by abnormally small size and low weight

iii. Identify associated multiple congenital anomalies listed in the clinical features

b. SRPS II (Majewski)

i. Markedly retarded endochondral ossification.

The chondrocytes in the physeal growth zones are markedly reduced in number and disorderly arranged.

ii. Lungs: hypoplasia as in type I

c. SRPS III (Verma-Naumoff)

i. Markedly retarded endochondral ossification as in type II. A single patient showed chondrocytic inclusions which are PAS reactive and diastase resistant.

ii. Lung: hypoplasia as in type I

iii. Identify associated multiple congenital anomalies which are less common in this type d. SRPS IV (Beemer-Langer)

i. Physeal growth zones showing a prominent but disorganized zone of hypertrophy. The vascuolar penetration of physeal cartilage is irregular.

ii. Lungs: hypoplasia as in type I

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib: 25%

b. Patient’s offspring: the patients will not survive to reproductive age

2. Prenatal diagnosis: not always possible to differentiate the subtypes

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a. Ultrasonography for SRPS I (Saldino-Noonan) i. Short fetal limbs

ii. Narrow thorax iii. Polydactyly

iv. Pointed metaphyses v. Dysplastic cystic kidneys vi. Congenital heart defect vii. Genital anomalies

b. Ultrasonography for SRPS II (Majewski)

i. With a positive family history of Majewski syndrome

a) Presence of short fetal limbs b) Other skeletal findings ii. Without a family history

a) Short fetal limbs

b) Disproportionately short tibia c) Very narrow fetal chest d) Short ribs

e) Bilateral postaxial polydactyly of the hands and feet

f) Median cleft lip and palate g) Polyhydramnios

h) Hydrops

i) Marked shortened humerus and femur j) Severe bowing and deformity of the bones of

the lower leg and forearm k) Hypoplastic lungs

l) Congenital heart defect m) Enlarged echogenic kidneys

n) Genital anomalies

c. Ultrasonography for SRPS III (Verma-Naumoff) i. Short fetal limbs

ii. Small/narrow thorax iii. Short thin ribs

iv. Polydactyly

v. Widened metaphyses with marginal spurs vi. Micromelia

d. Ultrasonography for SRPS IV (Beemer-Langer) i. Short fetal bones

ii. Small/narrow thorax iii. Short thin ribs

iv. Polydactyly e. Fetoscopy

i. To identify fetus with SRPS phenotype

ii. An invasive procedure currently replaced by ultrasonography

3. Management: supportive therapy only for these lethal entities

REFERENCES

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report of two cases. Am J Med Genet 14:115–123, 1983.

Benacerraf BR: Prenatal sonographic diagnosis of short rib-polydactyly syndrome type II, Majewski type. J Ultrasound Med 12:552–555, 1993.

Black IL, Fitzsimmons J, Fitzsimmons E, et al.: Parental consanguinity and the Majewski syndrome. J Med Genet 19:141–143, 1982.

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Chen H, Mirkin D, Yang S: De novo 17q paracentric inversion mosaicism in a patient with Beemer-Langer type short rib-polydactyly syndrome with special consideration to the classification of short rib polydactyly syndromes. Am J Med Genet 53:165–171, 1994.

Cooper CP, Hall CM: Lethal short-rib polydactyly syndrome of the Majewski type: a report of three cases. Radiology 144:513–517, 1982.

Corsi A, Riminucci M, Roggini M, et al.: Short rib polydactyly syndrome type III: histopathogenesis of the skeletal phenotype. Pediatr Dev Pathol 5:91–96, 2002.

Elçiog˘lu N, Karatekin G, Sezgin B, et al.: Short rib-polydactyly syndrome in twins: Beemer-Langer type with polydactyly. Clin Genet 50:159–163, 1996.

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Fig. 1. Radiograph of a neonate with Saldino-Noonan syndrome (SRPS I) showing extremely shortened horizontal ribs, very small and dysplastic vertebral bodies and iliac cones, and very short tubular bones with irregular metaphyses.

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

Fig. 3. Photomicrograph of humerus (SRPS I) shows markedly dis- rupted physeal growth zone by a large cartilage canal-like vascular fibrous tissue. In addition, there is a large premature ossification center (upper one third of the picture).

Fig. 4. A neonate with Majewski syndrome (SRPS II) showed hydrops, a large head, hairy forehead, small, malformed, and low-set ears, telecanthus, short nose, a flat nasal bridge, a central cleft upper and lower lips, short neck, short and narrow chest, markedly distend- ed abdomen with ascites, extremely short limbs with pre- and postaxial polydactyly, syndactyly, and brachydactyly.

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Fig. 8. Radiographs (SRPS II) showing extremely short, horizontal ribs, high clavicles, unremarkable spine and pelvis, premature ossification of the proximal epiphyses of the humeri, femora, and lateral cuboids. The tubular bones were extremely short, especially the mesomelic segments. The tibiae were disproportionately short and oval in shape.

Fig. 5. Mouth of the neonate in Fig. 4 showing lobulated tongue and mucosal frenular.

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

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

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Fig. 9. Respiratory system (necropsy) (SRPS II) showing a small lar- ynx with hypoplastic epiglottis (arrow) and remarkably small and hypoplastic lungs. The patient’s thymus is juxtaposed for comparison.

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

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

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Fig. 12. Radiographs of the skeletal system (SRPS III) showing extremely short and horizontal ribs, small dysplastic vertebral bodies and ilia, short tubular bones with widened metaphyses with longitudi- nal spurs

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

Fig. 14. Higher magnification of the chondrocytes in the resting carti- lage and the physeal zone of proliferation frequently show cytoplas- mic inclusions (PAS after diastase digestion) (SRPS III).

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Fig. 15. A fetus with Beemer-Langer syndrome showing macro- cephaly, cystic hygroma, severe micro/retrognathia with cleft palate, low-set and malformed ears, short limbs, narrow thorax, protuberant abdomen with an omphalocele, and polydactyly. The radiographs show short, horizontal ribs, small scapulae, relatively poorly ossified vertebral bodies, small ilia, short tubular bones with absence of metaphyseal spicules, bowed radii and ulnae, and postaxial polydactyly.

The ultrasonograph shows porencephalic cyst. The fetus also had a de novo paracentric inversion of chromosome 17q (q12;q25).

Fig. 17. Physeal growth zone of femur showing prominent but disor- ganized zone of hypertrophy (SRPS IV).

Fig. 16. Radiograph of another premature neonate (SRPS IV) showing extremely short and horizontal ribs, small dysplastic vertebral bodies, small iliac wings, and short tubular bone.