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1994-01-11-13 Pterygium syndrome, multiple lethal © Suma http://www.thefetus.net/

Pterygium syndrome, multiple lethal

Vincenzo Suma, MD, Alberto Marini, MD, Francesco Bellitti, PhD, Guglielmo Serpotta, MD, Riccardo Saia,MD

Address correspondence to: Vincenzo Suma, MD,Ultrasonic Service, Division of Obstetrics and Gynecology, Civilian Hospital, via Giustinioni 3, 35128 Padua, Italy. Ph: 39-49-8213481 Fax: 39-49-8213493.

Synonyms: None.

Definition: A syndrome characterized by multiple pterygia (chinto-sternum, cervical, axillary, antecubital, popliteal and crural), flexion contractures, skeletal abnormalities, hypoplastic heart and lungs, facial anomalies and cystic hygroma1,2.

Prevalence: Unknown; fewer than 200 cases reported.

Etiology: Probably related to an autosomal recessive inheritance3, but an X-linked recessive inheritance is also advanced4.

Pathogenesis: The data suggest that the syndrome combines the manifestations of a jugular lymphatic obstruction sequence with those of an early severe fetal akinesia sequence with two possible mechanisms: an abnormally fragile collagen constitution or an early fetal muscular "dystrophy"

Associated anomalies: Multiple pterygia, cystic hygroma, hypoplastic lungs and heart, skeletal abnormalities, facial anomalies, and growth retardation (Table 3).

Differential diagnosis: With a normal karyotype: lethal popliteal pterygium syndrome (Bartsocas-Papas syndrome), and Pena-Shokeir syndrome

Prognosis: Lethal.

Recurrence risk: 25% in the autosomal recessive syndrome.

Management: Pregnancy termination before viability. Standard obstetrical management after viability.

CODES = MESH Pterygium congenital, contracture congenital BDE 2274 MIM 253290, 265000, 312150 ICD9 228.1 CDC 228.100

Introduction

The multiple pterygium syndrome is a rare autosomal recessive disorder characterized by multiple pterygia (chin to sternum, cervical, axillary popliteal, crural, antecubital), flexion contractures, hypoplastic heart and lungs, skeletal abnormalities, facial anomalies (hypertelorism, epicanthic folds, flattened nose, micrognathia, and apparently low-set ears), and cystic hygroma. Two types have been described: a lethal form involving abortions and stillbirths and a non- lethal form appearing in children and adolescents.

Case report

A 30-year-old G woman was referred at 11 weeks of gestation for ultrasound evaluation. Her past obstetrical history was remarkable in that both her first and second pregnancies had been interrupted at 15 and 18 weeks, respectively, because of fetal spina bifida and myelomeningocele. At the time, pre- and post-conception treatment with folic acid was advised in view of future pregnancies. Her third and fourth pregnancies resulted in the birth of two healthy babies with no anomalies.

Since the current pregnancy was unplanned, the patient had not undergone preventive treatment with folic acid. Ultrasound examination with transabdominal and transvaginal probes revealed a single fetus, compatible with age, with a small cystic mass on the back of the neck (fig. 1,2). The diagnosis of cystic hygroma was formulated. Subsequent CVS showed a normal 46XX karyotype.

A repeat sonographic scan at 15 gestational weeks (fig. 3) evidenced the disappearance of the cystic hygroma and its substitution by fairly thick skin (pterygium). No fetal movements were observed.

Further ultrasonic examinations at 18 and 21 weeks showed the fetus in the same position. The upper and lower extremities were fixed, flexed and shortened. The feet were clubbed. The chest appeared narrow and deformed, and the vertebral column showed marked scoliosis of the cervico-thoracic region (fig. 4-7). The volume of amniotic fluid was increased.

After discussion with the couple, the pregnancy was terminated by prostaglandin perfusion.

Figura 1: Cystic mass at the back of the head on a transverse view (11 weeks).

Figura 2: Cystic mas at the back of the head on a longitudinal view (11 weeks).

Figura 3: Pterygium colli (15 weeks).

Figura 4: Longitudinal view of the chest and abdomen. The chest appears narrow and deformed (18 weeks).

Figura 5:Lower extremities showing talipes equino-varus (21 weeks)

Figura 6: Upper extremities showing flexion of the wrists (21 weeks).

Figura 7: View of the hands showing camptodacty ly (21 weeks)

Post-mortem findings

Physical examination of the child showed micrognathia, a small mouth, epicantal folds, and very short neck. Multiple pterygia involved the neck, axillae, antecubital, popliteal, crural and interphalangeal areas. The chest was short. Both feet were clubbed, and the anus was a blind pouch (fig. 8). In addition, radiographic studies showed multiple pterygia but no bony fusion (fig. 9).

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Figure 8: Post-mortem view showing micrognathia, hand and feet deformities and pterygia of joints.

Figura 9: Lateral X-ray showing no bony fusions and limb contractures.

Discussion

Prevalence

The incidence and prevalence of this syndrome are unknown. Reliable statistics concerning these aspects are not available; fewer than 200 cases have been reported.

Etiology

The syndrome is probably related to an autosomal recessive gene mutation. However, following the description of a family in which three male fetuses presenting a similar lethal multiple pterygium syndrome were born to mothers who were first cousins through the female line, an X-linked recessive inheritance was advanced. Therefore, in view of this possibility, all women with a family history of an affected male member should be monitored.

Pathogenesis

According to Hale, the limb pterygia syndromes may be classified as autosomal dominant or recessive form; the latter include two lethal forms: the lethal popliteal pterygium syndrome (Bartsocas-Papas syndrome) and the lethal multiple pterygium syndrome (Table 1). Subsequently, Hale et al. proposed the subdivision of the lethal multiple pterygium syndrome into three groups based on the age of onset on intrauterine growth retardation, the degree of neck swelling, and the presence or absence of bony fusions of the vertebral and long bones.

Table 1: Type of syndromes:

Dominant

Recessive

Popliteal pterygium syndrome
Antecubital pterygium syndrome
Multiple pterygium syndrome + ptosis + skeletal abnormalities

Multiple pterygium syndrome
Lethal multiple pterygium syndrome
Lethal popliteal pterygium syndrome (Bartsocas-Papas syndrome) + facial cleft
Popliteal pterygium syndrome + ectodermal dysplasia
Other conditions with limb pterygia
Kuskokwin syndrome
Mietens syndrome
Weyers syndrome
Roberts syndrome

Several mechanisms have been advanced to explain the pathogenesis of limb pterygia, the most notable manifestation of the lethal multiple pterygium syndrome. According to Hartwig et al5, an abnormally fragile collagen constituction is responsible for the lethal immobility, pterygia and many of the associated anomalies. Skin normally grows due to the stimuli exerted by the mechanical forces of the underlying tissues (i.e., bones) which grow outwardly, and thus follows the normal contour of the structure to which it is solidly attached.

The first fetal movements, which start at about 8 weeks development, are abrupt and uncoordinated, and may cause muscle fiber lacerations if the reticular fiber collagen is particularly fragile. Consequently, muscular disuse, atrophy, and fetal immobility will follow if the fetus is immobile. Fixed flexion positions of the joints and weak connections between the skin and underlying structures may be present. In this onset, the skin may grow along a shorter track than the structures to which it is attached. The decreased growth stimulus leads to the formation of multiple pterygia and a series of structural abnormalities (pulmonary hypoplasia, low-set ears, micrognathia, hand and foot deformities, abnormal bone modeling) known as the "fetal akinesia deformation sequence".

Following a histological study of the neuromuscular system of fetuses with the lethal multiple pterygium syndrome, Moerman et al more recently advanced that this syndrome combines the manifestations of a jugular lymphatic obstruction sequence with those of an early severe fetal akinesia sequence. The jugular lymphatic obstruction causes edema and cystic hygroma colli. Lymph vessels and muscles are both mesodermal structures; an early, genetically determined biochemical insult affecting these structures may cause an arrest in the development of muscle (primary aplasia) whose fibers are replaced by adipose tissue. This early "muscular dystrophy" most likely underlies the fetal akinesia sequence as part of the lethal multiple pterygium syndrome.

Diagnosis

The prenatal diagnosis of lethal multiple pterygium syndrome by means of ultrasonography is possible in the second trimester of gestation in most cases when there is a high index of suspicion due a previous occurrence1,9,14. However, normal ultrasound findings do not exclude the presence of an affected fetus, and since the syndrome may present an intrafamilial variability, fetoscopy may be needed. When the syndrome is instead sporadic, as in our case, the ultrasonographic findings that help formulate the diagnosis of lethal multiple pterygium syndrome from the 14-15 week of pregnancy are: 1) cystic hygroma at the back of the head and neck; 2) non-immune fetal hydrops; 3) short and fixed limbs, 4) lack of fetal movements, and 5) polyhydramnios.

Differential diagnosis

In the presence of a normal karyotype, the differential diagnosis should include lethal popliteal pterygium syndrome (Bartsocas-Papas syndrome) and Pena-Shokeir syndrome (Table 2).

Table 2: Differential diagnosis of lethal multiple pterygium syndrome.

Syndrome | Differences
Lethal popliteal | Pterygia only in the lower extremities.
Pterygium 7 | Cleft lip and palate with pitted lower lip.Genital abnormalities ( bifid scrotum, hypoplastic penis, cryptorchidism, hypoplastic labia )16.
Pena-Shokeir,type I | Many similarities are present, but multiple pterygia are absent.

Associated anomalies

Table 3: Associated anomalies

Cystic hygroma of the neck
Edema and hydrops
Multiple pterygia at all joints

chin-to-sternum

cervical
axillary
antecubital
popliteal
crural

Muscular-skeletal anomalies

flexion contracture of multiple joints
muscle atrophy/abdominal muscle hypoplasia
short stature
talipes as equinovarus
bony fusions: humero-ulnar, radio-ulnar, between
spine apophyses, between epiphyseal cartilage of the long bones.

Facial anomalies

hypertelorism
epicanthic folds

downward slanting palpebral fissures
flattened nasal bridge
micrognathia
low set ears
cleft palate
cleft upper lip (non mid-line)

Cardiac hypoplasia
Lung hypoplasia/agenesia
Small chest
Congenital hernia of the diaphragm
External genital hypoplasia /cryptorchidism
Hydranencephaly/porencephaly
Intestinal malrotation/atresia
Low birth weight (less than 3 percentile).

Prognosis

The condition is generally lethal in utero.

Recurrence risk

Since the syndrome has an autosomal recessive transmission, the estimated recurrence risk is 25%.

Obstetrical management

Determination of the fetal karyotype is indicated to exclude genetic syndromes (trisomy 21, 18, 13, and XXXXY syndromes). When the diagnosis is made before viability, the option of pregnancy termination should be offered to the patient. If the diagnosis is reached after viability, non aggressive management is recommended.

References

1. Chen H, Immuken L, Lachman R, et al: Syndrome of multiple pterygia, camptodactyly, facial anomalies hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies. Am J Med Genet 17:809-826, 1984.

2. Martin NJ, Hill JB, Cooper DH, et al:Lethal multiple pterygium syndrome, Three consecutive cases in one family. Am J Med Genet 24:295-304,1986.

3. Hall JG, Reed AD, Rosenbaum KN, et al: Limb pterygium syndrome. A review and report of eleven patients. Am J Med Genet 12:377-407, 1982.

4. Mc Keown CM, Harris R: An autosomal dominant pterygium syndrome. J Med Genet 25:96-106 ,1988.

5. Hartwig NG, Vermejj-Keets Chr, Brujin JA, et al: Case of lethal multiple pterygium syndrome with special reference to the origin of pterygia. Am J Med Genet 33:537-541,1989.

6. Moerman PH, Fryns JP, Carmelis A, et al: Pathatogenesis of the lethal multiple pterygium syndrome. Am J Med Genet 35:415-421, 1990.

7. Bartsocas CS, Papas CV: Popliteal pterygium syndrome. Am J Med Genet 9:222-226, 1972.

8. Pena SD, Shokeir BM: Syndrome of camptodactyly multiple ankyloses, facial anomalies and pulmonary hypoplasia: a lethal condition. J Pediatr 85:373-82, 1974.

9. Zeitune M., Fejgln M: Prenatal diagnosis of the pterygium syndrome. Prenat Diagn 8:l45-9, 1988.

10. Escobar V, Bixler D, Gleiser S, et al: Multiple pterygium syndrome. Am J Dis Child 132:609-611, 1978.

11. Chen H, Chang CH, Misra RP, et al: Multiple pterygium syndrome. Am J Med Genet 7:91-102, 1980.

12. Chen H, Immken L, Lachman R, et al: Syndrome of multiple pterygium. Am J Med Genet 17:809-26, 1984.

13. Tolmie JL, Patrick A, Yates J: A lethal multiple pterygium with apparent X-linked recessive inheritance. Am J Med Genet 27:913-917, 1987.

14. Hall JG: Editorial comment: The lethal multiple pterygium syndromes. Am J Med Genet 17;803-7, 1984.

15. Moessinger AC: Fetal akinesia deformation sequence: an animal model. Pediatrics 72:857-63, 1983.

16. Papadia F, Zimbalatti F, Gentile La Rosa C.: The Bartsocas-Papas syndrome: autosomal recessive form of popliteal pterygium syndrome in a male infant. Am J Med Genet 17:841-847,1984.

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