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Elaboration of the phenotypic changes of the upper limbs in the Neu-Laxova syndrome.

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American Journal of Medical Genetics 2O:l-11 (1985)
Elaboration of the Phenotypic Changes of
the Upper Limbs in the Neu-Laxova
Syndrome
LA. Shved, G.I. Lazjuk, and E.D. Cherstvoy
Byelorussian Postgraduate Medical Training Institute, Minsk Branch Institute of
Medical Genetics, Minsk, USSR
We present two new cases and data from a detailed study of the upper limbs
(structural changes, the state of peripheral nerves, arteries, muscles and bones) of
three stillborn infants with the Neu-Laxova syndrome. The morphogenesis of
many of the examined anatomical structures in these fetuses was anomalous. The
origin of these anomalies is discussed.
Key words: congenital malformations, Neu-Laxova syndrome, upper limbs, autosomal recessive
syndrome
INTRODUCTION
It is known [Neu et al, 1971; Laxova et al, 1972; PoGysilovh et al, 1976; Winter
et al, 1981; Fitch et al, 1982; Turkel et al, 19831 that the upper limbs of patients with
the Neu-Laxova syndrome are grossly abnormal. However, no data on the anatomical
structure of the limbs have been published; therefore, no pathogenetic hypothesis can
be offered. This impelled us to investigate anatomically the upper limbs of three
stillborn infants with the Neu-Laxova Syndrome.
MATERIAL AND METHODS
The upper limbs of three stillborn infants were studied [one case previously
published, Lazjuk et al, 19791. Postmortem radiographs of the arteries filled with a
suspension of carbonic lead in 3 % gelatin solution were obtained, and gross dissection
of nerves, muscles, and bones was made. The correlation of muscle length with
absolute and relative length of the corresponding segment of the limb was determined.
The muscles were examined histologically using hematoxylin-eosin, and sudan black
Received for publication July 12, 1984; revision received February 2, 1984.
Address reprint requests to Ur. I.A. Shved, Byelorussian Postgraduate Medical Training Institute, P.
Brovka str. 3, Minsk 220 714,'USSR.
@ 1985 Alan R. Liss, Inc.
2
Shved, Lazjuk, and Cherstvoy
staining. The upper limbs of ten stillborn and neonatally dead infants with no
malformations were taken as the control sample.
CASE REPORTS
Case 1
Previously reported by Lazjuk et a1 [ 19791.
Case 2
Stillborn male (the sib of Case 1) was born at 40 weeks. Birth weight, 1.520 g,
length 44 cm, occipital circumference 27 cm (Fig. 1). He had generalized subcutaneous edema, excessive extension of fat throughout his body, cranio-stenosis, a
sloping forehead, short palpebral fissures, hyper-telorism, apparently low-set ears,
short neck, micrognathia, macrostomia, and hypoplastic penis.
The upper limbs showed micromelia, rigid joints of the shoulders, flexion
contractures of elbow joints with forearm pronation, antecubital cutaneous pterygium,
ulnar deviation of hands, flexion contractures of fingers 2-5 with clinodactyly of
finger 5 , partial cutaneous syndactyly 2-4, hypoplastic and proximally positioned
thumbs.
The lower limbs showed flexion contracture of knee joints.
At autopsy the infant was noted to have a brain weight of 33 g (expected 25.5
g), lissencephaly, aplasia of the corpus callosum, hypoplasia of olfactory and optic
nerves, and aplasia of pyramidal tracts. The cerebellum weighed only 1.0 g and
lacked a vermis; lateral ventricles of the brain were dilated. The size of the globes
was normal. Anterior chamber of he eye was missing. The iris was conjoined with
the cornea and lens. There was persistence of primary corpus vitreum and dysplastic
retina.
Case 3
Stillborn female was delivered at 32 weeks. Abruption of placenta was noted at
delivery. The mother of the girl was 25 and the father was 31. They were unrelated.
Birth weight was 1516 g, length 39 cm, occipital circumference 24.5 cm.
The examination (Fig. 2) showed generalized subcutaneous edema with excessive extension of fat, a sloping forehead, hypertelorism, a broad nasal bridge,
micrognathia, macrostomia, short neck, cleft palate, hypoplastic external genitalia,
perineal anal ectopia, and shortness of the umbilical cord (29 cm) with aplasia of one
artery.
The upper limbs were short. There were rigid joints of the shoulders, flexion
contracture of elbow joints with forearm pronation, antecubital cutaneous pterygium,
flexion contracture of fingers 2-4 with cutaneous syndactyly, ulnar deviation of hands,
extension contracture of fingers 5 and radiocarpal articulation, clinodactyly of little
fingers, hypoplastic and proximally positioned thumbs.
The anomalies of the lower limbs included bilateral valgus deformity of feet
with “rocker bottom” appearance, hypoplasia of toes, partial syndactyly 2-3 of the
right foot.
Autopsy showed brain weighed 18.1 g, lissencephaly, aplasia of the corpus
callosum, undeveloped roof of the fourth ventricle of the brain, hypoplasia of the
Neu-Laxova Syndrome
3
Fig. 1 . Stillborn male with the Neu-Laxova syndrome (Case 2).
Fig. 2. Stillborn female with the Neu-Laxova syndrome (Case 3).
cerebellum with aplastic vermis, and aplasia of pyramidal tracts. The eyes showed
the absence of anterior chamber and the iris was conjoined with the lens. There was
persistence of primary corpus vitreum and lenticular artery and dysplastic retina,
pulmonary hypoplasia, and bifid uterus.
RESULTS
Peculiar changes of all six upper limbs included: shortness (6/6), rigidity of
shoulders and flexion contracture at elbow joint with forearm pronation (6/6), elbow
pterygium (6/6), extension contracture of radiocarpal articulation (2/6), flexion contracture of fingers 2-4 (6/6) and 5 (4/6), extension contracture of little finger (2/6),
clinodactyly of the latter (6/6), hypoplasia and proximal displacement of the first
finger (6/6), cutaneous syndactyly of fingers 2-4 (6/6), ulnar deviation of hands (4/
6), and severe hand edema (6/6) Fig. 3a,b).
Arteries
Postmortem radiographs of the arteries of four upper limbs showed a low
division of brachial into hypoplastic radial and ulnar artery (2/4) and the absence of a
superficial palmar arterial arch (414).
Nerves
Brachial plexus was formed from four spinal nerves (6/6); the musculocutaneous nerve arose from lateral (6/6) branch of the median nerve; the ulnar nerve was
fused for a short length (2/6) into a common trunk with the median nerve (Fig. 4a,b).
4
Shved, Lazjuk, and Cherstvoy
Fig. 3a,b. Upper limbs from one fetus.
Fig. 4a,b. The nerves of the upper limbs. Brachial plexus is formed by four spinal nerves; the musculocutaneous nerve arises from the lateral trunk of the median nerve (a,b); the nerves on palms and fingers
distribute normally (b).
Neu-Laxova Syndrome
5
Muscles
The changes in muscles (anomalies and/or variations) were present in all limbs
(Table I).
Besides the anomalies and variations given in the table, all cases showed
hypoplasia and disproportionate shortness (the discrepancy between muscle length
and the length of the corresponding segment of the limb) of biceps brachii, brachialis,
flexor carpi radialis and ulnaris, flexor digitorum profundis and superficialis, brachioradialis, and of extensor carpi radialis brevis and longus (fig. 5a-d). The degree
of defect in these muscles varied. However, it was more prominent in flexors of
forearm and fingers, though the shortness of the other muscles was slight and
compatible with findings in the control series. Two upper limbs with extensor
contracture at radiocarpal articulation showed slight shortness of extensor digitorum
and digiti minimi (Fig. 6), extensor indicis, extensor pollicis longus, and abductor
policis. Four limbs had an “excess” length of the corresponding extensors.
Rigidity of the anterior portion of elbow joint capsule and palmar portion of
capsules 11-IV (6/6) and/or V (416) of interphalangeal articulations was noted
consistently.
An excessive extension of fat into the hypodermic region of the limbs, between
the muscles, and under their fascia1 covering was observed in all cases. Microscopic
examination showed focal muscular fat degeneration, focal myolysis, cell proliferation of the endo- and perimysium and muscular lymphoid cell infiltration (Fig. 7a,b).
Fat tissue of palms and dorsal surface of the hands was severely edematous, which
was probably caused by lymphostasis most probably due to anomalous structure of
lymphatic vessels. However, further investigation is needed to confirm this
supposition.
Bones
In all cases the head of the humerus was deformed and hypoplastic (Fig. 8a),
this was also true of the cartilaginous part of the cavitas glenoidalis. Ulna was slightly
curved proximally with anterior and medial rotation of the proximal epiphysis. Its
relative length was less than in the control limbs. The radial border of the coronoid
process was maldeveloped. The head of radius was small and displaced anterior to
the lateral epicondyle. The capitellum humeris was undeveloped. complete anterior
dislocation of the head of the radius (216) or incomplete dislocation (4/6) was present
(Fig. 8b). Ossa metacarpalia and phalanges (of the first finger in particular) were
hypoplastic as well (low weight, decreased thickness), though relative length fitted
the control material. The middle phalanx of the 2nd finger (4/6) and digiti minimi (6/
6) was short; proximal and/or distal end of the latter was hypoplastic. Synostosis
(lack of separation) of 0s lunatum and triquetrum as well as of the 0s trapezoidum
and capitatum (2/6) was noted (Fig. 9a,b). Major and minor cavities of joints were
well formed.
DISCUSSION
These data suggest that in the Neu-Laxova syndrome many anatomical structures of the upper limbs are structurally anomalous. The changes of arteries and
nerves included structural variations, aplasia of the superficial arterial palmar arch
6
Shved, Lazjuk, and Cherstvoy
TABLE I. Incidence of Anomalies and Variations of Muscles of the Upper Limbs
Anomalies and variations
Muscles of the arm
Biceps brachii: doubling of the short head (three heads)
Musculus brachialis: low origin
Musculus coracobrachialis: partially fused with the short head of biceps brachii
Triceps: low origin of the medial head
Muscles of the forearm
Anterior muscles
Pronator teres: ulnar head aplasia
fused (lack of separation) with flexors carpi radialis
Flexor carpi radialis: aplasia anomalous insertion
Musculus palmaris longus: aplasia anomalous structure
Flexor digitorum superficialis: an accessory muscle portion
V finger tendon arises from IV tendon
Flexor digitorum profundus: V finger tendon arises from IV tendon
Radial muscles
Musculus brachioradialis: partially fused with m. brachialis
Extensor carpi radialis longus and brevis: a common muscular belly
Posterior muscles
Extensor digitorum: the doubling of the tendon of the IV finger
V finger tendon arises from IV tendon
Extensor digiti minimi: arises from extensor digitorum
doubling of the tendon
Abductor pollicis longus: a common muscular belly with a short extensor of the
latter
Extensor pollicis brevis: aplasia anomalous structure
Extensor pollicis longus: a common muscular belly with extensor indicis
Thenar_
muscles
~
_ _
Flexor pollicis brevis: aplasia
Opponens policis: aplasia
Abductor pollicis brevis: aplasia anomalous insertion
Adductor pollicis: anomalous structure, including the absence of separation into
heads
oblique head aplasia
Hypothenar muscles
Palmaris brevis: aplasia
Opponens digiti minimi: aplasia splits off from flexor digiti minimi
Incidence
216
216
616
616
416
416
216
416
416
216
216
216
216
616
616
216
316
616
316
216
316
316
516
616
616
216
216
516
316
216
Flexor digiti minimi: anomalous insertion
Abductor digiti minimi: high insertion
616
316
316
316
216
Lumbrical muscles
The first and the second: anomalous insertion
The fourth: aplasia
the doubling (2/ 6) ,anomalous insertion (216)
The first palmar interosseal muscles: anomalous insertion
216
216
416
216
Neu-Laxova Syndrome
7
Fig. 5a-d. Muscles of upper limbs. a, brachialis muscle (1); biceps brachii (2)with functional defect in
their length (they keep the forearm fixed in flexion); b, brachioradialis (l), extensor carpi radialis longus
and brevis (2), functional defect in length of brachioradialis; c, flexor digitorum profundus ( l ) , flexor
pollicis longus (2); d, tendons of flexor digitorum are cut.
and of the cervical spinal nerve of the brachial plexus. Muscle changes included
hypoplasias and aplasias (mostly of thenar and hypothenar muscles), supernumerary
muscles or supernumerary parts of muscles and other anomalies or structural variants.
Defective length of flexors of forearms and fingers and less commonly of the
extensors of the forearms and fingers was noted. The genesis of the shortness of these
8
Shved, Lazjuk, and Cherstvoy
Fig. 6 . The extensor digitorum and extensor digiti minimi (l), extensor carpi ulnaris (2): doubling of
tendon of the 5th finger extensor, unusual origin of the 5th finger tendon is formed from the tendon of
“supernumerary” 5th finger extensor; the extensor digiti minimi arises from the muscle belly of the
extensor digitorum; its tendon is doubled and hypoplastic.
Fig. 7a,b. Flexor digitorum superficialis. a, focal granular degeneration and myolysis of muscular
fibers, cellular proliferation of endo- and perimysium, infiltration by lymphoid cells (hcmatoxylin-eosin
stan, X90); b, focal extension of fat into muscle (sudan black staining, X35).
Neu-Laxova Syndrome
9
Fig. 8a,b. Bones of the limbs. a, proximal humerus with deformity of the head; b, hypoplastic
anteriorly dislocated head of radius; hypoplasia of ossa metacarpalia and phalangs. Clinodactyly of 5th
finger.
muscles is still unknown. Barash et a1 [ 19701 considered that the camptodactyly and
some of the positional deformities of the fingers in trisomy 18 might represent the
effects of relative fetal inactivity either due to a generalized systemic (metabolic?)
defect, a lack of proper innervation, or an intrinsic muscle defect. Perhaps in the
Neu-Laxova syndrome it is associated with inadequate linear growth of muscles,
although the cerebral anomalies, which are always present in this syndrome [Neu et
al, 1971; Laxova et al, 1972; Po$ysilovh et al, 1976; Lazjuk et al, 1979; Ostrovskaya
et al, 1978; Winter et al, 1981; Fitch et al, 19821 may cause growth abnormalities as
well as a number of other parts of the cerebroarthrodigital sequence [Scott et al,
19811. This supposition is confirmed by the shortness of the flexors of forearm and
fingers documented by us in other MCA syundromes (eg. trisomy 13 and trisomy 18
syndromes), in which a wide spectrum of changes in muscle structure of the upper
limbs [Aziz, 1979, 1981; Barash et al, 1970; Bersu et al, 1980; Pettersen et al, 1979;
Ramirez-Castro & Bersu, 19781 and in which CNS anomalies are practically common
[Bocquet, 1968; Taylor, 1968; Nedzved et al, 19741. Perhaps the shortness of forearm
flexors is responsible for the flexion contracture at elbow joint and the formation of
elbow pterygium, pronation of forearm, and anterior subluxation or dislocation of the
head of radius. The similar defective length of finger flexors may also cause flexion
contracture of hands. The anomalous structure of flexors of fingers 5 was noted twice
with only the distal (tendinous) part arising from the tendoon of the flexor of the 4th
finger being formed. If these cases showed aplasia of some hypothenar muscles, the
extensors of finger 5 prevailed functionally, which may have caused its extension
contracture. Clinodactyly of the little finger is most probably due to hypoplasia of the
medial margins of the middle phalanx. The muscles showed extensive fatty degeneration, which probably was a secondary change. This suppostion is confirmed to a
certain extent by the presence of lymphocytic infiltrates representing an inflammatory
reaction to the destruction of muscular tissue. However, the excessive presence of
10
Shved, Lazjuk, and Cherstvoy
Fig. 9a,b. Hand bones: complete synostosis of os lunatum-triquetrum (1) and trapexzoidum-capitaturn
(2).
fatty tissue throughout the infants’ body does not exclude a defect of fat metabolism
in this syndrome.
Usually there were changes of a number of bones in the upper limbs. Some of
them were secondary, resulting from functional defects of muscles which formed
persistent contractures (more often flexion ones) at the corresponding joints and
incorrect correlation of articular surfaces during intrauterine development. Bone
hypoplasia probably is due to a failure of periosteal growth, since relative length of
most bones due to enchondral growth was normal. The fact strengthens the viewpoint
of Fitch et al [1981] that the shortness of the digits in the Neu-Laxova syndrome is
due to syndactyly and not to a deficiency of the fingers. The shortness of some bones
evidently is due to a failure of enchondral growth, though the influence of muscular
contractures on their growth can not be excluded. Reduction in length and curve of
the ulna resulted in forearm shortness. Curry [1982], based on differences in the
limbs, slun and bone films, divided the Neu-Laxova syndrome into 3 groups. Bearing
in mind that our three cases represent similar gross changes of the upper limbs and
bones, we reserve our judgement on this classification.
The changes in many anatomical structures of the upper limbs probably are
caused by the influence of the mutant gene on their morphogenesis. Ramirez-Castro
and Bersu El9781 regarded some structural anomalies of the upper limbs in trisomy
18 as being associated with a defect in peripheral nerve development or tissue
necrosis. Aiz [ 19811 explained their origin by developmental retardation during early
stages of embryogenesis. The character of the anomalies of the anatomical structures
of the upper limbs in the Neu-Laxova syndrome (hypoplasia, aplasia, extra anatomical
structures, incomplete division of muscles, bones etc) represent changes in morphogenesis resulting from involvement of embryonal anlagen and/or their differentiation
including the failure to develope (indivision of muscles and bones) during the early
stages of embryogenesis.
Neu-Laxova Syndrome
11
CONCLUSIONS
1. In the Neu-Laxova syndrome the morphogenesis of many anatomical structures of the upper limbs is affected. The development of arteries, nerves, and bones
is affected to a lesser extent but to a greater extent in muscles, which together with
structural anomalies are exposed to fatty degeneration.
2. Some anomalies of anatomical structures of the upper limbs are primary and
probably due to the influence of anomalous recessive genes on their anlagen and/or
differentiation, including the failure to develop during the early stages of embryongenesis.
3. The contractures of the upper limbs and some other deformities are of
secondary (functional) character and are caused by muscualr anomalies, mainly their
defective length. Some of the bone amomalies may intensify the severity of limb
contractures.
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Edited by John M. Opitz and James F. Reynolds
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