852 Roberts syndrome is a rare hereditary disorder characterized by symmetrical reduction of all limbs and a unique cytogenetic abnormality of premature centromere separation, which dis- rupts the process of chromatid pairing.
GENETICS/BASIC DEFECTS
1. Inheritance: autosomal recessive
2. Associated with unique cytogenetic abnormality: prema- ture centromere separation
a. Disrupts the process of chromatid pairing
b. Responsible for the development of multiple structural anomalies observed in Roberts syndrome
3. Caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion
CLINICAL FEATURES
1. Craniofacial malformations: marked variability a. Bilateral cleft lip and cleft palate in severe cases b. No clefting of the lip or palate in some cases c. Hypertelorism secondary to widely spaced obits d. Ophthalmic manifestations
i. Exophthalmos due to shallow orbits ii. Microphthalmia
iii. Peter anomaly iv. Cloudy cornea
v. Cataracts e. Wide nasal bridge
f. Hypoplastic nasal alae
g. Hemangiomata of the lip, nose, face, or forehead h. Micrognathia
i. Dark scalp hair becomes thin and silvery blond 2. Limb defects
a. Phenotype varies from a complete absence of arms and legs with rudimentary digits to mild growth reduction in the limbs.
b. Limb reduction defects tend to be symmetric and more severely involved in the upper extremities than the lower extremities.
c. Presence of phocomelia
i. Tetraphocomelia: a prominent characteristic of the syndrome
ii. Two deficient limbs in 11% of cases iii. No phocomelia in 2% of cases
d. Often reduced number of fingers (oligodactyly) e. Radial aplasia or dysplasia common
f. Lack of 1st metacarpal, thumb, or first phalanx 3. Other associated anomalies
a. CNS anomalies i. Mental retardation ii. Microcephaly
iii. Hydrocephalus iv. Absent olfactory lobes
v. Calcification of the basal ganglia vi. Encephalocele
vii. Cranial nerve paralysis viii. Seizures
b. Congenital heart defects i. Atrial septal defect ii. Patent ductus arteriosus iii. Pulmonic stenosis
iv. Aortic stenosis v. AV canal defect c. Renal anomalies
i. Polycystic kidneys ii. Dysplastic kidneys iii. Horseshoe kidney
iv. Hydronephrosis v. Renal agenesis d. Gastrointestinal obstruction e. Splenogonadal fusion
f. Cryptorchidism g. Enlarged phallus h. Failure to thrive
i. Neoplasms
i. Sarcoma botryoides ii. Malignant melanoma 4. Prognosis
a. Severe cases
i. Often resulting in spontaneous abortions or still- births
ii. Few cases survive past one month of life b. Phenotypically milder cases
i. Requiring minimal to full time care depending on the degree of mental retardation
ii. May require surgical interventions to correct craniofacial and limb anomalies
5. Differential diagnosis a. SC phocomelia
i. Clinical characteristics a) Tetraphocomelia b) Silvery blond hair c) Facial hemangioma d) Hypoplastic nasal alae
ii. Originally thought to differ from Roberts syn- drome by:
a) Usual absence of midfacial clefting b) Prolonged survival
c) Lesser degree of mental and physical retar- dation
d) Relatively milder degree of phocomelia iii. Now considered to be the same entity as Roberts
syndrome (Roberts-SC phocomelia syndrome)
Roberts Syndrome
ROBERTS SYNDROME 853
b. TAR syndrome
i. Absent radii with thumbs present ii. Hypomegakaryocytic thrombocytopenia iii. Absent cleft palate
DIAGNOSTIC INVESTIGATIONS
1. Cytogenetics
a. Distinctive abnormality of the constitutive hete- rochromatin (the RS effect): premature centromere separation (PCS)
i. Detected in:
a) Fibroblasts and lymphocytes in neonates b) Chorionic villi and amniocytes in the fetus ii. Consists of “puffing” or “repulsion” of the con-
stitutive heterochromatin
a) Chromosome puffing most obvious at the large heterochromatic regions of chromo- somes 1, 9, and 16
b) Chromosome repulsion most evident at the short arms of the acrocentrics and the distal long arm of the Y chromosome
iii. A “rail-road-track” or “tram-track” appearance of the sister chromatids due to the absence of a constriction at the centromere in several other chromosomes
a) This phenomenon, called heterochromatin repulsion, is observed in cells of different tis- sue origin with several chromosomes in each metaphase showing a visible abnormality b) Most evident in chromosomes containing
the largest amount of heterochromatin b. Sporadic aneuploidy noted with the pattern of aneu-
ploidy different in each patient. The possible relation- ship between centromere “splaying” and aneuploidy has yet to be determined
c. Normal karyotypes lacking any microdeletion or chromosomal rearrangement from either leukocytes or fibroblasts in about a fifth of all cases
2. Radiography for phocomelia evaluation
a. Absence of the radius and fibula: the most common skeletal abnormalities in the upper and lower limbs b. Absent, short, deformed and /or hypoplastic ulna and
tibia: the second most common bone defects
c. Absent, short, deformed or hypoplastic humerus and femur: the third and least common abnormalities 3. Echocardiography for congenital heart defect 4. Renal ultrasound for renal anomalies 5. MRI of the brain for CNS anomalies
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib: 25%
b. Patient’s offspring: not increased (not surviving to reproduction in severe cases)
2. Prenatal diagnosis for pregnancies at risk a. Ultrasonography
i. Intrauterine growth retardation
ii. Bilateral phocomelia (tetraphocomelia in major- ity of cases) of varying degree
iii. Cleft lip and palate iv. Associate anomalies
a) Hydrocephalus
b) Congenital heart defects c) Renal anomalies
b. Confirmed by characteristic disjunction of cen- tromeres in amniocytes or CVS
3. Management
a. Special education b. Cornea grafting c. Corrective surgery
i. Cleft lip/palate ii. Limb defects d. Prosthetic devices
i. For underdeveloped or missing limbs ii. Used to increase independence
REFERENCES
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Fig. 1. The G-banded metaphase spread from fibroblast culture of a male infant with Roberts syndrome showing characteristic heterochro- matin separation: puffing of the centromeric heterochromatin of some chromosomes and splaying of the Yqh region (arrows). The patient had profound psychomotor retardation, corneal clouding, and tetraphocomelia.
Fig. 2. A newborn with Roberts syndrome variant showing bilateral cleft lip and cleft palate, phocomelia, club hands with an appendage-like thumb on the right and a missing thumb on the left. The infant also had intrauterine growth retardation, hydrocephalus, cloudy cornea, AV canal heart defect, and normal lower extremities. Cytogenetic studies revealed no premature centromere separation. The mother took Diflucan during pregnancy and the teratogenic etiology was a possibility.
ROBERTS SYNDROME 855
