*100800 ACHONDROPLASIA [ACH]

[jamie at gdb.org]

*RECORD*
*FIELD* NO
100800

*FIELD* TI
*100800 ACHONDROPLASIA [ACH]

*FIELD* LD
New-Structure. This entry has been restructured according to a new
editorial policy.  A statement on the new editorial policy can be
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Achondroplasia is the most frequent form of short-limb dwarfism.
Affected individuals exhibit short stature caused by rhizomelic
shortening of the limbs, characteristic facies with frontal bossing
and mid-face hypoplasia, exaggerated lumbar lordosis, limitation of
elbow extension, genu varum, and trident hand.

Achondroplasia is an autosomal dominant disorder; a majority of cases
are sporadic, the result of a de novo mutation.  The causative gene
has been located on the distal end of the short arm of chromosome 4
(Velinov et al., 1994; Le Merrer et al., 1994; Francomano et al.,
1994).

*FIELD* PT
CLINICAL FEATURES
Whereas many conditions that cause short stature have inappropriately
been called achondroplasia in the past, the phenotype of this
osteochondrodysplasia is so distinctive and so easily identified
clinically and radiologically at birth that confusion should not
occur.  It is characterized by a long, narrow trunk, short
extremities, particularly in the proximal (rhizomelic) segments, a
large head with frontal bossing, hypoplasia of the midface and a
trident configuration of the hands.  Hyperextensibility of most
joints, especially the knees, is common, but extension and rotation
are limited at the elbow.  A thoracolumbar gibbus is typically
present at birth, but usually gives way to exaggerated lumbar
lordosis when the child begins to ambulate.  Mild to moderate
hypotonia is common, and motor milestones are usually delayed.
Intelligence is normal unless hydrocephalus or other central nervous
system complications arise.  In 13 achondroplastic infants, Hecht
et al. (1991) found that cognitive development was average and did
not co.
rrelate with motor development which typically was delayed.  It
was noteworthy that reduced mental capacity correlated with evidence
of respiratory dysfunction detected by polysomnography.

In children, caudad narrowing of the interpeduncular distance, rather
than the normal caudad widening, and a notchlike sacroiliac groove
are typical radiologic features.  Also in children, epiphyseal
ossification centers show a circumflex or chevron seat on the
metaphysis.  Limb shortening is especially striking in the proximal
segments, e.g., the humerus; hence the description rhizomelic ('root
limb').  The radiologic features of true achondroplasia and much
concerning the natural history of the condition were presented by
Langer et al. (1967) on the basis of a study of 101 cases and by Hall
(1988).

True megalencephaly occurs in achondroplasia and has been speculated
to indicate effects of the gene other than those on the skeleton
alone (Dennis et al., 1961).  Disproportion between the base of the
skull and the brain results in internal hydrocephalus in some cases.
The hydrocephalus may be caused by increased intracranial venous
pressure due to stenosis of the sigmoid sinus at the level of the
narrowed jugular foramina (Pierre-Kahn et al., 1980).  Hall et al.
(1982) pointed out that the large head of the achondroplastic fetus
creates an increased risk of intracranial bleeding during delivery.
They recommended that in the management of achondroplastic infants
ultrasonography be done at birth and at 2, 4 and 6 months of age to
establish ventricular size, the presence or absence of hydrocephalus,
and possible intracranial bleed.  They stated the impression that
some achondroplasts have only megalencephaly, others have true
communicating hydrocephalus, and yet others have dilated ventricles
without hydrocephalus.  Nelson et al. (1988) concluded that brainstem
compression is common in achondroplasia and may account in part for
the abnormal respiratory function.

Hecht et al. (1988) .
reviewed the subject of obesity in
achondroplasia, concluding that it is a major problem which, whatever
its underlying cause, aggravates the morbidity associated with lumbar
stenosis and contributes to the nonspecific joint problems and to the
possible early cardiovascular mortality in this condition.

Homozygosity for the achondroplasia gene results in a severe disorder
of the skeleton with radiologic changes qualitatively somewhat
different from those of the usual heterozygous achondroplasia; early
death results from respiratory embarrassment from the small thoracic
cage and neurologic deficit from hydrocephalus (Hall et al., 1969).
Yang et al. (1977) reported upper cervical myelopathy in a
homozygote.

Horton et al. (1988) found that the epiphyseal and growth plate
cartilages have a normal appearance histologically, and the major
matrix constituents exhibit a normal distribution by immunostaining;
however, morphometric investigations have indicated that the growth
plate is shorter than normal and that the shortening is greater in
homozygous than in heterozygous achondroplasia, suggesting a gene
dosage effect.  Stanescu et al. (1990) reported histochemical,
immunohistochemical, electron microscopic, and biochemical studies on
upper tibial cartilage from a case of homozygous achondroplasia.  No
specific abnormality was defined.  Aterman et al. (1983) expressed
puzzlement at the striking histologic changes in homozygous
achondroplasia despite the virtual absence of changes in the
heterozygote.  They pointed out that histologic studies in the
heterozygote at a few weeks or months of age have not been done.
They suggested that because of similarities between what they called
PHA (presumed homozygous achondroplasia) and thanatophoric dwarfism
(187600), some cases of the latter condition may be due to a
particularly severe mutation at the achondroplasia locus.

Hypochondroplasia (146000) may be caused by an allele at the
achondroplasia locus.  The evidence comes from o.
bservations of a
presumed genetic compound in the offspring of an achondroplastic
father and a hypochondroplastic mother who exhibited growth
deficiency and radiographic abnormalities of the skeleton that were
much more severe than those typically seen in achondroplasia
(McKusick et al., 1973; Sommer et al., 1987) and somewhat less severe
than those of the ACH homozygote.  Young et al. (1992) described
lethal short-limb dwarfism in the offspring of a father with
spondyloepiphyseal dysplasia congenita (SEDC; 183900) and a mother
with achondroplasia.  Young et al. (1992) suggested that the infant
was a double heterozygote for the 2 dominant genes rather than a
compound heterozygote.  It was considered unlikely that SEDC and
achondroplasia are allelic because of the evidence that most, if not
all, cases of SEDC result from mutation in the type II collagen gene
(COL2A1; 120140), whereas this gene has been excluded as the site of
the mutation in achondroplasia.

In a presentation of adult genetic skeletal dysplasias found in the
Museum of Pathological Anatomy in Vienna, Beighton et al. (1993)
pictured the skeleton of a 61-year-old man with achondroplasia who
died of transverse myelitis.  Randolph et al. (1988) reported an
achondroplastic patient who developed classic ankylosing spondylitis
(106300).  There is no fundamental connection between the 2
disorders.  The importance of the observation is mainly to indicate
that back problems in achondroplasts can be due to causes other than
the underlying disease.

*FIELD* GT
MODE OF INHERITANCE
Achondroplasia is inherited as an autosomal dominant with essentially
complete penetrance.  About seven-eighths of cases are the result of
new mutation, there being a considerable reduction of effective
reproductive fitness.

Paternal age effect on mutation was noted by Penrose (1955).  Stoll
et al. (1982) reported advanced paternal age in sporadic cases
ascertained through the French counterpart of LPA (Little People of
America), APPT (.
Association des Personnes de Petite Taille).
Thompson et al. (1986) found that, on average, the severity of
achondroplasia tends to be reduced with increasing parental age.  It
is doubtful that a recessive form of achondroplasia,
indistinguishable from the dominant form, exists.  Documentation of
the diagnosis is inadequate in most reports of possible recessive
inheritance.

Cohn and Weinberg (1956) reported affected twins with an affected
sib.  (This may have been achondrogenesis, e.g., 200600).  Chiari
(1913) reported affected half-sibs whose father had achondroplasia.
Two first cousins, whose mothers were average-statured sisters, had
undoubted achondroplasia (Wadia, 1969).  Most dominants show
sufficient variability to account for observations such as these on
the basis of reduced penetrance but such is not the case with
achondroplasia.

Gonadal mosaicism (or spermatogonial mutation) is a possible
explanation for affected sibs from normal parents.  Bowen (1974)
described a possible instance of gonadal mosaicism; 2 daughters of
normal parents had achondroplasia.  One of the daughters had 2
children, one of whom was also achondroplastic.  Fryns et al. (1983)
reported 3 achondroplastic sisters born to normal parents.  Philip
et al. (1988) described the case of a man who had 3 daughters with
classic achondroplasia, by 2 different women.

Affected cousins could be due to the coincidence of two independent
mutations.  Such was probably the case, in McKusick's opinion, in the
second cousins once removed reported by Fitzsimmons (1985).  Reiser
et al. (1984) reviewed 6 families with unexpected familial recurrence
and hypothesized that these recurrences were simply the result of two
independent chance events.  Dodinval and Le Marec (1987) reported 2
families, each with 2 cases of achondroplasia.  In 1 family, a girl
and her great aunt were affected; in the other, male and female first
cousins.  Both germinal mosaicism and paternal age effect appear to
have their basis in .
the way spermatogonia are replenished, a feature
that distinguishes gametogenesis in the male from that in the female.
As outlined by Clermont (1966), spermatogonia go through a few
mitotic divisions before embarking on the meiotic divisions that lead
to mature sperm.  Some of the products of the mitotic divisions are
returned to the 'cell bank' to replenish the supply of spermatogonia.
Mutations occurring during DNA replication can, therefore,
accumulate, providing a basis for paternal age effect and for
germinal mosaicism.  Hoo (1984) suggested a small insertional
translocation as a possible mechanism for recurrent achondroplasia in
sibs with normal parents.

The severe phenotype of the homozygote for the ACH gene and the
possibility that hypochondroplasia represents an allelic disorder
were discussed in connection with the discussion of clinical features
of achondroplasia.

MAPPING INFORMATION
Strom (1984) and Eng et al. (1985) purported to find abnormality of
the type II collagen gene in achondroplasia.  If such a defect is
present, one might expect ocular abnormality in achondroplasia
inasmuch as type II collagen is present in vitreous.  SED congenita
was a more plausible candidate for a structural defect of type II
collagen because it is a dominant disorder that combines skeletal
dysplasia with vitreous degeneration and deafness (experimental
studies with antibodies to type II collagen indicate that this
collagen type is represented in the middle ear); subsequently,
defects were in fact found in the COL2A1 gene in SEDC.  The report by
Eng et al. (1985) was withdrawn (see retraction, Eng et al., 1986)
because figures, 'which were generated in the laboratory of C. Strom
and C. Eng, were improperly assembled and therefore cannot be used to
support the conclusions of the article.'  Francomano and Pyeritz
(1988) excluded COL2A1 as the site of the mutation in achondroplasia
by use of probes spanning the gene in an analysis of genomic DNA from
49 affected persons and.
 2 multiplex families.  No gross
rearrangements were seen on Southern blot analysis, and linkage
studies in the multiplex families demonstrated discordant inheritance
of achondroplasia and COL2A1 alleles.  Evidence against linkage to
COL2A1 has been presented before by Ogilvie et al. (1986). From their
studies, Finkelstein et al. (1991) concluded that mutations at the
chondroitin sulfate proteoglycan core protein (CSPGCP) locus do not
cause achondroplasia or pseudoachondroplasia (177170).

Edwards et al. (1988) commented on a report, made at the national
meeting of the Neurofibromatosis Foundation, of 2 individuals with
achondroplasia and neurofibromatosis (162200) who had translocations
involving the long arm of chromosome 17.  In both cases the
breakpoint was at the region consistent with localization of the
neurofibromatosis gene by linkage studies; a third case of coincident
achondroplasia and neurofibromatosis was also mentioned.  Korenberg
et al. (1989) and Pulst et al. (1990) demonstrated by linkage
analysis that the achondroplasia locus does not map between the 2
groups of markers flanking the gene for neurofibromatosis-1 on human
chromosome 17.  Verloes et al. (1991) observed connatal neuroblastoma
in an infant with achondroplasia and suggested that the
achondroplasia gene may be located on the short arm of chromosome 1
where the neuroblastoma gene (256700) appears to be situated.

By linkage studies using DNA markers, Velinov et al. (1994) and
Le Merrer et al. (1994) mapped the gene for achondroplasia and
hypochondroplasia to the distal area of the short arm of chromosome 4
(4p16.3).  Francomano et al. (1994) likewise mapped the ACH gene to
4p16.3, using 18 multigenerational families with achondroplasia and 8
anonymous dinucleotide repeat polymorphic markers from this region.
No evidence of genetic heterogeneity was found.  Analysis of a
recombinant family localized the ACH locus to the 2.5-Mb region
between D4S43 and the telomere.

MOLECULAR GENETICS
Iden.
tification of the genetic defect in achondroplasia has been
elusive, but now that the gene has been assigned to a specific
location on 4p (Le Merrer et al., 1994; Velinov et al., 1994;
Francomano et al., 1994), cloning of the gene and identification of
mutations should not be far off.

*FIELD* DG
The diagnosis is based on the typical clinical and radiologic
features; the delineation from severe hypochondroplasia may be
arbitrary.

*FIELD* CM
Recommendations for follow-up and management were reviewed at the
first international symposium on achondroplasia (Nicoletti et al.,
1988) and by Horton and Hecht (1993).  The recommendations included:
measurements of growth and head circumference using growth curves
standardized for achondroplasia (Horton et al., 1978); careful
neurologic examinations (including CT, MRI, somatosensory evoked
potentials and polysomnography) and surgical enlargement of the
foramen magnum in cases of severe stenosis; management of frequent
middle ear infections and dental crowding; measures to control
obesity starting in early childhood; growth hormone therapy (Horton
et al., 1992), which is still experimental, and lengthening of the
limb bones; tibial osteotomy or epiphysiodesis of the fibular growth
plate to correct bowing of the legs; lumbar laminectomy for spinal
stenosis which typically manifests in early adulthood; delivery of
pregnant women with achodroplasia by cesarean section; and prenatal
detection of affected fetuses by ultrasound.

*FIELD* PG
The prevalence of achondroplasia is uncertain; previous estimates are
undoubtedly incorrect because of misdiagnosis.  For example, Wallace
et al. (1970) reported 2 female sibs as examples of achondroplasia;
both died in the neonatal period and showed, in addition to
chondrodystrophy, central harelip, hypoplastic lungs, and
hydrocephalus.  Without radiographic studies it is impossible to
identify the nature of this condition, but it is certainly not true
achondroplasia; Jeune asphyxiating thoracic.
 dystrophy (208500),
thanatophoric dwarfism, and achondrogenesis are each possibilities.

Using modern diagnostic criteria, Gardner (1977) estimated the
mutation rate at 0.000014.  Orioli et al. (1986) reported on the
frequency of skeletal dysplasias among 349,470 births (live and
stillbirths).  The prevalence rate for achondroplasia was between 0.5
and 1.5/10,000 births.  The mutation rate was estimated to be between
1.72 and 5.57 x 10(-5) per gamete per generation.  The stated range
is a consequence of the uncertainty of diagnosis in some cases.  (The
thanatophoric dysplasia/achondrogenesis group had a prevalence
between 0.2 and 0.5/10,000 births.  Osteogenesis imperfecta had a
prevalence of 0.4/10,000 births.  Only 1 case of diastrophic
dysplasia was identified.)  In the county of Fyn in Denmark, Andersen
and Hauge (1989) determined the prevalence of generalized bone
dysplasias by study of all children born in a 14-year period.  The
figures, which they referred to as 'point-prevalence at birth,'
showed that achondroplasia was less common than generally thought
(1.3 per 100,000), while osteogenesis imperfecta (21.8), multiple
epiphyseal dysplasia tarda (9.0), achondrogenesis (6.4),
osteopetrosis (5.1), and thanatophoric dysplasia (3.8) were found to
be more frequent.  Stoll et al. (1989) found a mutation rate of 3.3 x
10(-5) per gamete per generation.  In Spain, Martinez-Frias et al.
(1991) found a frequency of achondroplasia of 2.53 per 100,000 live
births.  Total prevalence of autosomal dominant malformation
syndromes was 12.1 per 100,000 live births.

*FIELD* HI
It is of historic interest that Weinberg (1912), of Hardy-Weinberg
law fame, noted in the data collected by Rischbieth and Barrington
that sporadic cases were more often last-born than first-born.

*FIELD* SA
See also: Beighton and Bathfield (1981); Cohen et al. (1967); Durr
(1968); Fremion et al. (1984); Hall et al. (1979); Maroteaux and Lamy
(1964); Morch (1941); Morgan and Young (1980); Murdoch et al.
. (1970);
Oberklaid et al. (1979); Opitz (1984); Pauli et al. (1983, 1984);
Penrose (1957); Pyeritz et al. (1987); Rimoin et al. (1970); Siebens
et al. (1978).

*FIELD* RF
Andersen, P. E., Jr. and Hauge, M.: Congenital generalised bone
dysplasias: a clinical, radiological, and epidemiological survey. J.
Med. Genet. 26: 37-44, 1989.

Aterman, K.; Welch, J. P.; and Taylor, P. G.: Presumed homozygous
achondroplasia: a review and report of a further case. Path. Res.
Pract. 178: 27-39, 1983.

Beighton, P. and Bathfield, C. A.: Gibbal achondroplasia. J. Bone
Joint Surg. 63: 328-329, 1981.

Beighton, P.; Sujansky, E.; Patzak, B.; and Portele, K. A.: Genetic
skeletal dysplasias in the Museum of Pathological Anatomy, Vienna.
Am. J. Med. Genet. 47: 843-847, 1993.

Bowen, P.: Achondroplasia in two sisters with normal parents. Birth
Defects Orig. Art. Ser. X(12): 31-36, 1974.

Chiari, H.: Ueber familiaere Chondrodystrophia foetalis. Muenchen.
Med. Wschr. 60: 248-249, 1913.

Clermont, Y.: Renewal of spermatogonia in man. Am. J. Anat. 118: 509-
524, 1966.

Cohen, M. E.; Rosenthal, A. D.; and Matson, D. D.: Neurological
abnormalities in achondroplastic children. J. Pediat. 71: 367-376,
1967.

Cohn, S. and Weinberg, A.: Identical hydrocephalic achondroplastic
twins. Subsequent delivery of single sibling with same abnormality.
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Dennis, J. P.; Rosenberg, H. S.; and Alvord, E. C., Jr.:
Megalencephaly, internal hydrocephalus and other neurological aspects
of achondroplasia. Brain 84: 427-445, 1961.

Dodinval, P. and Le Marec, B.: Genetic counselling in unexpected
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954, 1987.

Durr, D. K.: Eine neue Dysostoseform mit Mikromelie bei zwei
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Edwards, J. H.; Huson, S.; and Ponder, B.: Neurofibromatosis.
(Letter). Lancet II: 330 only, 1988.

Eng, C. E. L.; Pauli, R. M.; and Strom, C. M.: Nonrandom association
of a type II procollagen.
 genotype with achondroplasia. Proc. Nat.
Acad. Sci. 82: 5465-5469, 1985.

Eng, C. E. L.; Pauli, R. M.; and Strom, C. M.: Nonrandom association
of a type II procollagen genotype with achondroplasia. Proc. Nat.
Acad. Sci. 83: 5354 only, 1986. Retraction.

Finkelstein, J. E.; Doege, K.; Yamada, Y.; Pyeritz, R. E.; Graham, J.
M., Jr.; Moeschler, J. B.; Pauli, R. M.; Hecht, J. T.; and
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A.; Turner, C. E.; Taylor, E.; Meyers, D. A.; Blanton, S. H.; Murray,
J. C.; McIntosh, I.; and Hecht, J. T.: Localization of the
achondroplasia gene to the distal 2.5 Mb of human chromosome 4p. Hum.
Molec. Genet. in press: 1994.

Francomano, C. A. and Pyeritz, R. E.: Achondroplasia is not caused by
mutation in the gene for type II collagen. Am. J. Med. Genet. 29: 955
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Fremion, A. S.; Garg, B. P.; and Kalsbeck, J.: Apnea as the sole
manifestation of cord compression in achondroplasia. J. Pediat. 104:
398-401, 1984.

Fryns, J. P.; Kleczkowska, A.; Verresen, H.; and van den Berghe, H.:
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lbus, M. S.; Graham, C. B.; Pagon, R. A.; Luthy, D.
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Hecht, J. T.; Hood, O. J.; Schwartz, R. J.; Hennessey, J. C.;
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Horton, W. A.; Hecht, J. T.; Hood, O. J.; Marshall, R. N.; Moore, W.
V.; and Hollowell, J. G.: Growth hormone therapy in achondroplasia.
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-438, 1978.

Hoo, J. J.: Alternative explanations for recurrent achondroplasia in
siblings with normal parents. Clin. Genet. 25: 553-554, 1984.

Korenberg, J. R.; Barker, D.; Fain, P.; Graham, J.; Pribyl, T.; and
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neurofibromatosis 1. (Abstract). Cytogenet. Cell Genet. 51: 1025
only, 1989.

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Le.
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Human Achondroplasia: A Multidisciplinary Approach. New York: Plenum
Press. 1988. Pp. 3-9.

Oberklaid, F.; Danks, D. M.; Jensen, F.; Stace, L.; and Rosshandler,
S.: Achondroplasia and hyperchondroplasia: comments on frequency,
mutation rate, and radiological features in skull and spine. J. Med.
Genet. 16: 140-146, 1979.

Ogilvie, D.; Wordsworth, P.; Thompson, E.; and Sykes, B.: Evidence
against the structural gene encoding type II collagen (COL2A1) as the
mutant locus in achondroplasia. J. Med. Genet. 23: 19-22, 1986.

Opitz.
, J. M.: 'Unstable premutation' in achondroplasia: penetrance vs
phenotrance. (Editorial). Am. J. Med. Genet. 19: 251-254, 1984.

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prevalence rates for the skeletal dysplasias. J. Med. Genet. 23: 328-
332, 1986.

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*FIELD* CS
   Skel:     Osteochondrodysplasia.
   Growth:   Short-limb dwarfism identifiable at birth.
             Mean male adult height: 131 cm.
             Mean female height: 124 cm.
             Obesity.
   Head:     Frontal bossing.
             Megalencephaly.
   Facies:   Midfacial hypoplasia.
             Low nasal bridge.
   Eyes:     Strabismus.
   Ears:     Conductive or sensorineural hearing loss.
             Recurrent otitis media in infancy and childhood.
   Resp:     Respiratory insufficiency.
             Upper airway obstruction .
   Spine:    Lumbar gibbus in infancy.
             Exaggerated lumbar lordosis during childhood and
             adulthood.
   Joints:   Limited elbow and hip extension.
   Limbs:    Trident hand.
             Brachydactyly.
             Limited extension at elbows.
             Genu varum.
             Bowleg.
             Rhizomelia.
   Neuro:    Hydrocephalus occasional.
             Mild hypotonia in infancy and early childhood.
             Lumbar spinal stenosis common.
             Occasional thoracic or cervical spinal stenosis.
             Radiculopathy.
             Brain stem compression.
   Misc:     Paternal age mutation effect.
   Radiology:     Cuboidal vertebral bodies.
             Progressive lumbar interpeduncular narrowing after first
             year.
             Vertebral canal narrows in cranio-caudal direction.
             Notch-like sacroiliac groove.
             .
Metaphyseal flaring.
             Circumflex or chevron seated epiphyseal ossification
             centers on the metaphysis.
             Short narrow femoral neck.
             Vertebral scalloping.
             Wide intervertebral discs.
             Foraminal narrowing.
             Flat roofed acetabula.
             Small foramen magnum.
             Short cranial base.
             Early sphenooccipital closure.
   Inheritance:   Autosomal dominant with complete penetrance; most
                  (7/8) cases new mutations.

*FIELD* OLDNO
10080

*FIELD* ED
Last: 94/3/23
pfoster: 94/3/23
steinman: 94/2/4
carol: 94/3/16
mimadm: 94/3/15

 

---------------------

_______________________________________________________________________________ 
                           A. Jamie Cuticchia, Ph.D.

                   Assistant Professor of Medical Genetics
    Director of Data Acquisition and Curation Operations, Genome Data Base
_______________________________________________________________________________
                        
                   Johns Hopkins University School of Medicine
                  2024 E. Monument Street, Baltimore  MD  21205

(410) 614-0438  Phone                                        (410) 614-0434 Fax                                 jamie at gdb.org
________________________________________________________________________________