604 Lethal multiple pterygium syndrome (LMPS) is a lethal hereditary disorder characterized by a distinct constellation of multiple anomalies, consisting of multiple pterygia, flexion con- tractures of multiple joints, characteristic facial appearance, cys- tic hygroma, hydrops, and pulmonary and cardiac hypoplasia.
GENETICS/BASIC DEFECTS
1. Inheritance: possible heterogeneity a. Autosomal recessive inheritance b. Possible X-linked recessive inheritance
2. Classification by Hall (1982, 1984) and Entezami et al.
(1998)
a. Based on the following concominant abnormalities i. Age of onset of intrauterine growth retardation ii. Timing and extent of neck swelling
iii. Presence or absence of bony fusions and bone modeling errors
b. Type I (Gillin-Pryse-Davis syndrome) i. Multiple pterygia
ii. Pulmonary hypoplasia iii. Genital anomalies
iv. Facial anomalies
v. Strongly flexed extremities with a reduced mus- cle mass
c. Type II (Chen syndrome) i. Multiple pterygia ii. Hygroma colli iii. Facial anomalies
iv. Undermodeled long bones, with shortened extremities
v. Cartilaginous fusion of joints and bony fusion of the spinous processes of the vertebrae
vi. Polyhydramnios
vii. Hypoplastic lungs and heart viii. Diaphragmatic hernia
d. Type III (van Regemorter syndrome) i. Multiple pterygia
ii. Pulmonary hypoplasia iii. Facial anomalies
iv. Thin extremities with reduced muscle mass v. Fusions of the long tubular bones
e. Type IV (Herva syndrome) i. Multiple pterygia
ii. Degeneration of the anterior horn cells of the spinal cord
iii. Found particularly in Finland
3. Classification by De Die-Smulders et al. (1990) a. Early LMPS
i. A group with presumed genetic heterogeneity ii. Lethality in the second trimester
iii. Hydrops fetalis iv. Cystic hygroma
b. Late LMPS
i. Survival into the third trimester ii. Absence of fetal hydrops c. Finnish type LMPS
i. Feta hydrops from the 15th gestational week ii. Lethality at average gestation of 29 weeks iii. Occasional pterygia of the neck and elbows
iv. Distinct neuropathologic findings 4. Pathogenesis
a. Combination of the following two sequences i. Fetal akinesia deformation sequence
a) Resulting from myoneural dysfunction (gen- eralized amyoplasia) and/or intrauterine growth constraint leading to fetal akinesia b) Fetal akinesia, in turn, leading to growth
retardation, pulmonary hypoplasia, short umbilical cord, limb positional defects, and facial anomalies
ii. Jugular lymphatic obstruction sequence: delay in development of the connection between jugular lymph sacs and the internal jugular vein result- ing in dilatation of tributary lymphatics and peripheral lymphedema
b. Fragile collagen proposed as a possible pathogenesis
CLINICAL FEATURES
1. Prenatal history
a. Nonimmune fetal hydrops b. Diminished fetal activity c. Maternal hydramnios
d. Often presented with fetal demise 2. Characteristic facial features
a. Ocular hypertelorism
b. Antimongoloid slant of the palpebral fissures c. Epicanthal folds
d. Markedly flattened nasal bridge with hypoplastic nasal alae
e. Micrognathia f. Cleft palate
g. Apparently low-set malformed ears 3. Neck
a. Short
b. Cystic hygroma 4. Chest
a. Small chest b. Hypoplastic lungs c. Hypoplastic heart 5. Multiple pterygia
a. Symmetrical b. Sites
i. Chin-to-sternum ii. Cervical
iii. Axillary iv. Antecubital
v. Crural vi. Popliteal 6. Other limb anomalies
a. Multiple contractures: always present b. Camptodactyly
c. Calcaneovalgus foot deformities 7. Gastrointestinal anomalies
a. Intestinal malrotation b. Short bowel
c. Thin colon d. Colonic atresia
e. Absent vermiform appendix 8. Genitourinary anomalies
a. Hydronephrosis
b. Unilateral renal dysplasia c. Cryptorchidism
9. Other associated anomalies a. Kyphoscoliosis
b. Near complete absence of diaphragmatic muscle c. Aortic coarctation
d. Absent abdominal wall muscle e. Adrenal hypoplasia
f. Short umbilical cord g. Rare cerebral anomalies
i. Hydranencephaly ii. Holoprosencephaly
iii. Dilated ventricles with intracerebral cyst
DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. Craniofacial abnormalities i. Scalp edema
ii. Microbrachycephaly iii. Flattened mandibular angle
b. Hypoplasia and undermodeling of the bones i. Thin crowded ribs
ii. Markedly hypoplastic scapulae
iii. Hypoplastic iliac wings, ischia and pubic bones iv. Lack of normal curvature at the cervico-thoracic
junction c. Bony fusion
i. Marked bony fusion of posterior spinous processes
ii. Radio-ulnar synostosis
2. Histologic studies of the skeletal system
a. Cartilaginous and bony fusion of the spinous processes b. Fusion of epiphyseal cartilages of distal humerus and
proximal ulna
c. Poorly developed joint space d. An abnormal growth plate
e. Weak safranin staining of the resting cartilages f. Placenta
i. Scalloped chorionic villi
ii. Intravillous trophoblast invaginations g. Muscular and neural abnormalities 3. Chromosome analysis: normal
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Autosome recessive inheritance: 25%
ii. X-linked recessive inheritance: 50% risk of having an affected brother if the mother is a carrier b. Patient’s offspring: a lethal entity not surviving to
reproductive age 2. Prenatal diagnosis
a. Ultrasonography: possible i. Nonimmune fetal hydrops ii. Cystic hygroma
iii. Diminished fetal activity iv. Short and fixed limbs
v. Maternal hydramnios
vi. Other ultrasonographically detectable anomalies a) Diaphragmatic hernia
b) Scoliosis c) Pterygia 3. Management: a lethal entity
REFERENCES
Anthony J, Mascarenhas L, O’Brien J, et al.: Lethal multiple pterygium syn- drome. The importance of fetal posture in mid-trimester diagnosis by ultrasound: discussion and case report. Ultrasound Obstet Gynecol 3:212–216, 1993.
Brink DS, Luisiri A, Grange DK: Case report: lethal multiple pterygium syn- drome. Pediatr Pathol Mol Med 22:461–470, 2003.
Chen H, Chang CH, Misra RP, et al.: Multiple pterygium syndrome. Am J Med Genet 7:91–102, 1980.
Chen H, Immken L, Lachman R, et al.: Syndrome of multiple pterygia, campto- dactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet 17:809–826, 1984.
Clementi M, Notari L, Tenconi R: Lethal multiple pterygium syndrome: impor- tance of fetal physical examination. Am J Med Genet 57:119–120, 1995.
Cox PM, Brueton LA, Bjelogrlic P, et al.: Diversity of neuromuscular pathology in lethal multiple pterygium syndrome. Pediatr Dev Pathol 6:59–68, 2003.
de Die-Smulders CE, Schrander-Stumpel CT, Fryns JP: The lethal multiple pterygium syndrome: a nosological approach. Genet Couns 1:13–23, 1990.
de Die-Smulders CE, Vonsee HJ, Zandvoort JA, et al.: The lethal multiple pterygium syndrome: prenatal ultrasonographic and postmortem find- ings; a case report. Eur J Obstet Gynecol Reprod Biol 35:283–289, 1990.
Elias S, Boelen L, Simpson JL: Syndromes of camptodactyly, multiple ankylo- sis, facial anomalies, and pulmonary hypoplasia. Birth Defects Original Article Series 14(6B):243–251, 1978.
Entezami M, Runkel S, Kunze J, et al.: Prenatal diagnosis of a lethal multiple pterygium syndrome type II. Case report. Fetal Diagn Ther 13:35–38, 1998.
Escobar V, Weaver D: Popliteal pterygium syndrome: a phenotypic and genetic analysis. J Med Genet 15:35–42, 1978.
Francesco P, Nicola L: Nosological difference between the Bartsocas-Papas syndrome and lethal multiple pterygium syndrome. Am J Med Genet 29:699–700, 1988.
Froster UG, Stallmach T, Wisser J, et al.: Lethal multiple pterygium syndrome:
suggestion for a consistent pathological workup and review of reported cases. Am J Med Genet 68:82–85, 1997.
Froster-Iskenius UG, Curry C, Philp M, et al.: Brief clinical report: an unusual bandlike web in an infant with lethal multiple pterygium syndrome. Am J Med Genet 30:763–769, 1988.
Gericke GS: Fragile collagen and the lethal multiple pterygium syndrome: does heat stress play a role? Am J Med Genet 38:630–633, 1991.
Gillin ME, Pryse-Davis J: Pterygium syndrome. J Med Genet 13:249–251, 1976.
Hall JG: The lethal multiple pterygium syndromes. Am J Med Genet 17:803–807, 1984.
Hall JG, Reed SD, Rosenbaum KN, et al.: Limb pterygium syndromes: A review and report of eleven patients. Am J Med Genet 12:377–409, 1982.
Hartwig NG, Vermeij-Keers C, Bruijn JA, et al.: Case of lethal multiple ptery- gium syndrome with special reference to the origin of pterygia. Am J Med Genet 33:537–541, 1989.
Hertzberg BS, Kliewer MA, Paulyson-Nunez K: Lethal multiple pterygium syndrome: antenatal ultrasonographic diagnosis. J Ultrasound Med 19:657–660, 2000.
Herva R, Leisti J, Kirkinen P, et al.: A lethal autosomal recessive syndrome of multiple congenital contractures. Am J Med Genet 20:431–439, 1985.
Hogge WA, Golabi M, Filly RA, et al.: The lethal multiple pterygium syndromes:
is prenatal detection possible? Am J Med Genet 20:441–442, 1985.
Isaacson G, Gargus JJ, Mahoney MJ: Brief clinical report: lethal multiple pterygium syndrome in an 18-week fetus with hydrops. Am J Med Genet 17:835–839, 1984.
Lakshminarayana P, Jegatheesan T, Venkataraman P: Lethal multiple ptery- gium syndrome. Indian Pediatr 29:1305–1309, 1992.
Lockwood C, Irons M, Troiani J, et al.: The prenatal sonographic diagnosis of lethal multiple pterygium syndrome: a heritable cause of recurrent abor- tion. Am J Obstet Gynecol 159:474–476, 1988.
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.
Mbakop A, Cox JN, Stormann C, et al.: Lethal multiple pterygium syndrome: report of a new case with hydranencephaly. Am J Med Genet 25:575–579, 1986.
Meizner I, Hershkovitz R, Carmi R, et al.: Prenatal ultrasound diagnosis of a rare occurrence of lethal multiple pterygium syndrome in two siblings.
Ultrasound Obstet Gynecol 3:432–436, 1993.
Meyer-Cohen J, Dillon A, Pai GS, et al.: Lethal multiple pterygium syndrome in four male fetuses in a family: evidence for an X-linked recessive sub- type? Am J Med Genet 82:97–99, 1999.
Moerman P, Fryns JP, Cornelis A, et al.: Pathogenesis of the lethal multiple pterygium syndrome. Am J Med Genet 35:415–421, 1990.
Sciarrone A, Verdiglione P, Botta G, et al.: Prenatal diagnosis of lethal multiple pterygium syndrome in mid-pregnancy. Ultrasound Obstet Gynecol 12:218–219, 1998.
Spearritt DJ, Tannenberg AE, Payton DJ: Lethal multiple pterygium syndrome:
report of a case with neurological anomalies. Am J Med Genet 47:45–49, 1993.
Tolmie JL, Patrick A ,Yates JR: A lethal multiple pterygium syndrome with appar- ent X-linked recessive inheritance. Am J Med Genet 27:913–919, 1987.
Turnpenny PD, Hole R: The first description of lethal pterygium syndrome with facial clefting(Bartsocas-Papas syndrome) in 1600. J Med Genet 37:314–315, 2000.
Van Regemorter N, Wilkin P, Englert Y, et al.: Lethal multiple pterygium syn- drome. Am J Med Genet 17:827–834, 1984.
Fig. 1. The macerated 32-week stillborn (A,B) with Chen syndrome showing multiple pterygia involving the neck, axillae, antecubital, crural, popliteal, and interphalangeal areas, hygroma coli, and facial anomalies (hypertelorism, antimongoloid slant of the palpebral fis- sures, a shortened nose, depressed nasal bridge and tip of the nose, a long philtrum, a receding chin, apparently low-set and malformed ears). Contractures of the fingers were present with ulnar deviation of the hands. Polyhydramnios and fetal hydrops were noted by ultra- sonography at 30 weeks of gestation. Autopsy showed hypoplastic lungs and heart and a large left diaphragmatic hernia (containing intestine, pancreas, and part of the stomach and ascites). Radiographs (C,D) and postmortem section (E) revealed a large cystic hygroma, hypoplastic vertebral bodies, fusion of the posterior elements extend- ed from the cervical into the midthoracic spine, angulated cervicotho- racic junction, and undermodeled long bones. Representative section of the elbow (F) showed fusion of epiphyseal cartilages of the distal humerus and proximal ulna resulting in bending of the proximal por- tion of the ulna and a deficient joint space. The resting cartilage (G) was distinctly demarcated from the physeal growth plate, which showed slightly retarded but normally arranged chondrocytic column.
Fig. 2. A malformed macerated 28-week fetus (A,B) with Chen syn- drome showing impressive skin webbing at the neck, axillae, ante- cubital, crural, and popliteal areas, and abnormal facies (markedly flattened nasal bridge with anteverted and hypoplastic nasal alae, low-set ears, and a small mouth with cleft soft palate). In addition, there were contractures of the hands and fingers and rocker bottom feet. The prenatal ultrasound at 25 weeks of gestation (C) showed a large cystic hygroma at the back of the head. Radiographs (D,E) revealed massive edema of the scalp contiguous with the neck ptery- gia, hypoplastic vertebral bodies, multiple fusions of the posterior elements of the cervical and lumbosacral spine bodies, and incipient fusion of the radius and ulna bilaterally. Post mortem study revealed markedly hypoplastic lungs and heart.
Fig. 3. A 19-week fetus with Chen syndrome (A,B) showing a large cystic hygroma, detected by prenatal ultrasonography, multiple ptery- gia involving neck, axillae, elbows, fingers, and knees with contrac- tures, illustrated by radiographs (C,D). Distinctive facial features include hypertelorism, flat nasal bridge, cleft palate, and microg- nathia. Postmortem study revealed hypoplastic lungs and heart, fusion of cartilage of the elbow joints, and hypoplastic cervical vertebral bodies with posterior elements beginning to come together but were not yet fused.
Fig. 4. A fetus with lethal multiple pterygium (A,B) syndrome show- ing multiple pterygia involving neck, axilla, elbows, and knees asso- ciated with multiple contractures, illustrated by radiographs (C,D).
There were hypertelorism, small nose, micrognathia and microg- nathia.
Fig. 5. A stillbirth with lethal multiple pterygium syndrome showing flexion of all 4 limbs with multiple pterygia involving neck, axillae, elbows, and knees, short neck, and cystic hygroma colli. There were antimongoloid slant of the palpebral fissures, hypertelorism, flat nasal bridge, micrognathia, and high arched palate. The upper extremities were held in extreme flexion with ulnar deviation of both hands and camptodactyly. The lower limbs were rotated externally and flexed in a crossed position with bilateral calcaneus deformities of the feet.
Postmortem findings include multiloculated cystic hygroma, hypoplastic lungs and kyphoscoliosis.
