*100800 ACHONDROPLASIA [ACH]
jamie at gdb.org
jamie at gdb.org
Wed Mar 30 10:42:21 EST 1994
*100800 [7mACH[mONDROPLASIA [[7mACH[m]
New-Structure. This entry has been restructured according to a new
editorial policy. A statement on the new editorial policy can be
found under menu item 3 of the GDB entry screen or by retrieving a
special policy statement entry in OMIM with '000000.'
[7mAch[mondroplasia 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.
[7mAch[mondroplasia 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.,
Whereas many conditions that cause short stature have inappropriately
been called [7mach[mondroplasia 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 [7mach[mondroplastic infants, Hecht
et al. (1991) found that cognitive development was average and did
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 [7mach[mondroplasia 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
True megalencephaly occurs in [7mach[mondroplasia 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 [7mach[mondroplastic fetus
creates an increased risk of intracranial bleeding during delivery.
They recommended that in the management of [7mach[mondroplastic 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 [7mach[mondroplasts 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 [7mach[mondroplasia and may account in part for
the abnormal respiratory function.
Hecht et al. (1988) .
reviewed the subject of obesity in
[7mach[mondroplasia, 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 [7mach[mondroplasia gene results in a severe disorder
of the skeleton with radiologic changes qualitatively somewhat
different from those of the usual heterozygous [7mach[mondroplasia; 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
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 [7mach[mondroplasia, 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 [7mach[mondroplasia. No
specific abnormality was defined. Aterman et al. (1983) expressed
puzzlement at the striking histologic changes in homozygous
[7mach[mondroplasia 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 [7mach[mondroplasia) and thanatophoric dwarfism
(187600), some cases of the latter condition may be due to a
particularly severe mutation at the [7mach[mondroplasia locus.
Hypochondroplasia (146000) may be caused by an allele at the
[7mach[mondroplasia locus. The evidence comes from o.
bservations of a
presumed genetic compound in the offspring of an [7mach[mondroplastic
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 [7mach[mondroplasia
(McKusick et al., 1973; Sommer et al., 1987) and somewhat less severe
than those of the [7mACH[m 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 [7mach[mondroplasia. 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
[7mach[mondroplasia 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 [7mach[mondroplasia.
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 [7mach[mondroplasia who
died of transverse myelitis. Randolph et al. (1988) reported an
[7mach[mondroplastic 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 [7mach[mondroplasts can be due to causes other than
the underlying disease.
MODE OF INHERITANCE
[7mAch[mondroplasia 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
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
[7mach[mondroplasia tends to be reduced with increasing parental age. It
is doubtful that a recessive form of [7mach[mondroplasia,
indistinguishable from the dominant form, exists. Documentation of
the diagnosis is inadequate in most reports of possible recessive
Cohn and Weinberg (1956) reported affected twins with an affected
sib. (This may have been [7mach[mondrogenesis, e.g., 200600). Chiari
(1913) reported affected half-sibs whose father had [7mach[mondroplasia.
Two first cousins, whose mothers were average-statured sisters, had
undoubted [7mach[mondroplasia (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
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 [7mach[mondroplasia. One of the daughters had 2
children, one of whom was also [7mach[mondroplastic. Fryns et al. (1983)
reported 3 [7mach[mondroplastic sisters born to normal parents. Philip
et al. (1988) described the case of a man who had 3 daughters with
classic [7mach[mondroplasia, 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, e[7mach[m with 2 cases of [7mach[mondroplasia. 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 [7mach[mondroplasia in
sibs with normal parents.
The severe phenotype of the homozygote for the [7mACH[m gene and the
possibility that hypochondroplasia represents an allelic disorder
were discussed in connection with the discussion of clinical features
Strom (1984) and Eng et al. (1985) purported to find abnormality of
the type II collagen gene in [7mach[mondroplasia. If such a defect is
present, one might expect ocular abnormality in [7mach[mondroplasia
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 [7mach[mondroplasia
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 [7mach[mondroplasia 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 [7mach[mondroplasia or pseudo[7mach[mondroplasia (177170).
Edwards et al. (1988) commented on a report, made at the national
meeting of the Neurofibromatosis Foundation, of 2 individuals with
[7mach[mondroplasia 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
[7mach[mondroplasia and neurofibromatosis was also mentioned. Korenberg
et al. (1989) and Pulst et al. (1990) demonstrated by linkage
analysis that the [7mach[mondroplasia 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 [7mach[mondroplasia and suggested that the
[7mach[mondroplasia 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 [7mach[mondroplasia and
hypochondroplasia to the distal area of the short arm of chromosome 4
(4p16.3). Francomano et al. (1994) likewise mapped the [7mACH[m gene to
4p16.3, using 18 multigenerational families with [7mach[mondroplasia and 8
anonymous dinucleotide repeat polymorphic markers from this region.
No evidence of genetic heterogeneity was found. Analysis of a
recombinant family localized the [7mACH[m locus to the 2.5-Mb region
between D4S43 and the telomere.
tification of the genetic defect in [7mach[mondroplasia 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.
The diagnosis is based on the typical clinical and radiologic
features; the delineation from severe hypochondroplasia may be
Recommendations for follow-up and management were reviewed at the
first international symposium on [7mach[mondroplasia (Nicoletti et al.,
1988) and by Horton and Hecht (1993). The recommendations included:
measurements of growth and head circumference using growth curves
standardized for [7mach[mondroplasia (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 [7mach[modroplasia by cesarean section; and prenatal
detection of affected fetuses by ultrasound.
The prevalence of [7mach[mondroplasia is uncertain; previous estimates are
undoubtedly incorrect because of misdiagnosis. For example, Wallace
et al. (1970) reported 2 female sibs as examples of [7mach[mondroplasia;
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
[7mach[mondroplasia; Jeune asphyxiating thoracic.
thanatophoric dwarfism, and [7mach[mondrogenesis are e[7mach[m 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 [7mach[mondroplasia 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/[7mach[mondrogenesis 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 [7mach[mondroplasia was less common than generally thought
(1.3 per 100,000), while osteogenesis imperfecta (21.8), multiple
epiphyseal dysplasia tarda (9.0), [7mach[mondrogenesis (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 [7mach[mondroplasia of 2.53 per 100,000 live
births. Total prevalence of autosomal dominant malformation
syndromes was 12.1 per 100,000 live births.
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.
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.
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).
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
[7mach[mondroplasia: a review and report of a further case. Path. Res.
Pract. 178: 27-39, 1983.
Beighton, P. and Bathfield, C. A.: Gibbal [7mach[mondroplasia. 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.: [7mAch[mondroplasia 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-
Cohen, M. E.; Rosenthal, A. D.; and Matson, D. D.: Neurological
abnormalities in [7mach[mondroplastic children. J. Pediat. 71: 367-376,
Cohn, S. and Weinberg, A.: Identical hydrocephalic [7mach[mondroplastic
twins. Subsequent delivery of single sibling with same abnormality.
Am. J. Obstet. Gynec. 72: 1346-1348, 1956.
Dennis, J. P.; Rosenberg, H. S.; and Alvord, E. C., Jr.:
Megalencephaly, internal hydrocephalus and other neurological aspects
of [7mach[mondroplasia. Brain 84: 427-445, 1961.
Dodinval, P. and Le Marec, B.: Genetic counselling in unexpected
familial recurrence of [7mach[mondroplasia. Am. J. Med. Genet. 28: 949-
Durr, D. K.: Eine neue Dysostoseform mit Mikromelie bei zwei
Geschwistern. Helv. Paediat. Acta 23: 184-194, 1968.
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 [7mach[mondroplasia. 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 [7mach[mondroplasia. 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
Francomano, C. A.: Analysis of the chondroitin sulfate proteoglycan
core protein (CSPGP) gene in [7mach[mondroplasia and pseudo[7mach[mondroplasia.
Am. J. Hum. Genet. 48: 97-102, 1991.
Fitzsimmons, J. S.: Familial recurrence of [7mach[mondroplasia. Am. J.
Med. Genet. 22: 609-613, 1985.
Francomano, C. A.; Ortiz de Luna, R. I.; Hefferon, T. W.; Bellus, G.
A.; Turner, C. E.; Taylor, E.; Meyers, D. A.; Blanton, S. H.; Murray,
J. C.; McIntosh, I.; and Hecht, J. T.: Localization of the
[7mach[mondroplasia gene to the distal 2.5 Mb of human chromosome 4p. Hum.
Molec. Genet. in press: 1994.
Francomano, C. A. and Pyeritz, R. E.: [7mAch[mondroplasia is not caused by
mutation in the gene for type II collagen. Am. J. Med. Genet. 29: 955
Fremion, A. S.; Garg, B. P.; and Kalsbeck, J.: Apnea as the sole
manifestation of cord compression in [7mach[mondroplasia. J. Pediat. 104:
Fryns, J. P.; Kleczkowska, A.; Verresen, H.; and van den Berghe, H.:
Germinal mosaicism in [7mach[mondroplasia: a family with 3 affected
siblings of normal parents. Clin. Genet. 24: 156-158, 1983.
Gardner, R. J. M.: A new estimate of the [7mach[mondroplasia mutation
rate. Clin. Genet. 11: 31-38, 1977.
Hall, J. G.: The natural history of [7mach[mondroplasia. In Nicoletti, B.;
Kopits, S. E.; Ascani, E.; and McKusick, V. A. (eds.): Human
[7mAch[mondroplasia: A Multidisciplinary Appro[7mach[m. New York: Plenum Press.
1988. Pp. 3-10.
Hall, J. G.; Dorst, J. P.; Taybi, H.; Scott, C. I., Jr.; Langer, L.
O., Jr.; and McKusick, V. A.: Two probable cases of homozygosity for
the [7mach[mondroplasia gene. Birth Defects Orig. Art. Ser. V(4): 24-34,
Hall, J. G.; Go.
lbus, M. S.; Graham, C. B.; Pagon, R. A.; Luthy, D.
A.; and Filly, R. A.: Failure of early prenatal diagnosis in classic
[7mach[mondroplasia. Am. J. Med. Genet. 3: 371-375, 1979.
Hall, J. G.; Horton, W.; Kelly, T.; and Scott, C. I.: Head growth in
[7mach[mondroplasia: use of ultrasound studies. (Letter). Am. J. Med.
Genet. 13: 105 only, 1982.
Hecht, J. T.; Hood, O. J.; Schwartz, R. J.; Hennessey, J. C.;
Bernhardt, B. A.; and Horton, W. A.: Obesity in [7mach[mondroplasia. Am.
J. Med. Genet. 31: 597-602, 1988.
Hecht, J. T.; Thompson, N. M.; Weir, T.; Patchell, L.; and Horton, W.
A.: Cognitive and motor skills in [7mach[mondroplastic infants: neurologic
and respiratory correlates. Am. J. Hum. Genet. 41: 208-211, 1991.
Horton, W. A. and Hecht, J. T.: The chondrodysplasias. In Royce, P.
M. and Steinmann, B. (eds.): Connective Tissue and Its Heritable
Disorders: Molecular, Genetic, and Medical Aspects. New York: Wiley-
Liss. 1993. Pp. 641-675.
Horton, W. A.; Hecht, J. T.; Hood, O. J.; Marshall, R. N.; Moore, W.
V.; and Hollowell, J. G.: Growth hormone therapy in [7mach[mondroplasia.
Am. J. Med. Genet. 42: 667-670, 1992.
Horton, W. A.; Hood, O. J.; M[7mach[mado, M. A.; and Campbell, D.: Growth
plate cartilage studies in [7mach[mondroplasia. In Nicoletti, B.; Kopits,
S. E.; Ascani, E.; and McKusick, V. A. (eds.): Human [7mAch[mondroplasia:
A Multidisciplinary Appro[7mach[m. New York: Plenum Press. 1988. Pp. 81-
Horton, W. A.; Rotter, J. I.; Rimoin, D. L.; Scott, C. L.; and Hall,
J. G.: Standard growth curves for [7mach[mondroplasia. J. Pediatr. 93: 435
Hoo, J. J.: Alternative explanations for recurrent [7mach[mondroplasia in
siblings with normal parents. Clin. Genet. 25: 553-554, 1984.
Korenberg, J. R.; Barker, D.; Fain, P.; Graham, J.; Pribyl, T.; and
Pulst, S.-M.: [7mAch[mondroplasia is not tightly linked to the locus for
neurofibromatosis 1. (Abstract). Cytogenet. Cell Genet. 51: 1025
Langer, L. O., Jr.; Baumann, P. A.; and Gorlin, R. J.:
[7mAch[mondroplasia. Am. J. Roentgen. 100: 12-26, 1967.
Merrer, M.; Rousseau, F.; Legeai-Mallet, L.; Landais, J.-C.;
Pelet, A.; Bonaventure, J.; Sanak, M.; Weissenb[7mach[m, J.; Stoll, C.;
Munnich, A.; and Maroteaux, P.: A gene for [7mach[mondroplasia--
hypochondroplasia maps to chromosome 4p. Nature Genet. 6: 314-317,
Maroteaux, P. and Lamy, P.: [7mAch[mondroplasia in man and animals. Clin.
Orthop. 33: 91-103, 1964.
Martinez-Frias, M. L.; Cereijo, A.; Bermejo, E.; Lopez, M.; Sanchez,
M.; and Gonzalo, C.: Epidemiological aspects of mendelian syndromes
in a Spanish population sample: I. Autosomal dominant malformation
syndromes. Am. J. Med. Genet. 38: 622-625, 1991.
McKusick, V. A.; Kelly, T. E.; and Dorst, J. P.: Observations
suggesting allelism of the [7mach[mondroplasia and hypochondroplasia
genes. J. Med. Genet. 10: 11-16, 1973.
Morch, E. T.: Chondrodystrophic dwarfs in Denmark. Op. Ex Domo Biol.
Hered. Hum. U. Hafniensis. 3: 1941.
Morgan, D. F. and Young, R. F.: Spinal neurological complications of
[7mach[mondroplasia: results of surgical treatment. J. Neurosurg. 52: 463-
Murdoch, J. L.; Walker, B. A.; Hall, J. G.; Abbey, H.; Smith, K. K.;
and McKusick, V. A.: [7mAch[mondroplasia--a genetic and statistical
survey. Ann. Hum. Genet. 33: 227-244, 1970.
Nelson, F. W.; Hecht, J. T.; Horton, W. A.; Butler, I. J.; Goldie, W.
D.; and Miner, M.: Neurological basis of respiratory complications in
[7mach[mondroplasia. Ann. Neurol. 24: 89-93, 1988.
Nicoletti, B.; Kopits, S. E.; Ascani, E.; and McKusick, V. A. (eds.):
Human [7mAch[mondroplasia: A Multidisciplinary Appro[7mach[m. New York: Plenum
Press. 1988. Pp. 3-9.
Oberklaid, F.; Danks, D. M.; Jensen, F.; Stace, L.; and Rosshandler,
S.: [7mAch[mondroplasia 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 [7mach[mondroplasia. J. Med. Genet. 23: 19-22, 1986.
, J. M.: 'Unstable premutation' in [7mach[mondroplasia: penetrance vs
phenotrance. (Editorial). Am. J. Med. Genet. 19: 251-254, 1984.
Orioli, I. M.; Castilla, E. E.; and Barbosa-Neto, J. G.: The birth
prevalence rates for the skeletal dysplasias. J. Med. Genet. 23: 328-
Pauli, R. M.; Conroy, M. M.; Langer, L. O., Jr.; McLone, D. G.;
Naidich, T.; Franciosi, R.; Ratner, I. M.; and Copps, S. C.:
Homozygous [7mach[mondroplasia with survival beyond infancy. Am. J. Med.
Genet. 16: 459-473, 1983.
Pauli, R. M.; Scott, C. I.; Wassman, E. R., Jr.; Gilbert, E. F.;
Leavitt, L. A.; Ver Hoeve, J.; Hall, J. G.; Partington, M. W.; Jones,
K. L.; Sommer, A.; Feldman, W.; Langer, L. O.; Rimoin, D. L.; Hecht,
J. T.; and Lebovitz, R.: Apnea and sudden unexpected death in infants
with [7mach[mondroplasia. J. Pediat. 104: 342-348, 1984.
Penrose, L. S.: Parental age and mutation. Lancet II: 312-313, 1955.
Penrose, L. S.: Parental age in [7mach[mondroplasia and mongolism. Am. J.
Hum. Genet. 9: 167-169, 1957.
Philip, N.; Auger, M.; Mattei, J. F.; and Giraud, F.: [7mAch[mondroplasia
in sibs of normal parents. J. Med. Genet. 25: 857-859, 1988.
Pierre-Kahn, A.; Hirsch, J. F.; Renier, D.; Metzger, J.; and
Maroteaux, P.: Hydrocephalus and [7mach[mondroplasia: a study of 25
observations. Child's Brain 7: 205-219, 1980.
Pulst, S.-M.; Graham, J. M., Jr.; Fain, P.; Barker, D.; Pribyl, T.;
and Korenberg, J. R.: The [7mach[mondroplasia gene is not linked to the
locus for neurofibromatosis 1 on chromosome 17. Hum. Genet. 85: 12-
Pyeritz, R. E.; Sack, G. H., Jr.; and Udvarhelyi, G. B.:
Thoracolumbosacral laminectomy in [7mach[mondroplasia: long-term results
in 22 patients. Am. J. Med. Genet. 28: 433-444, 1987.
Randolph, L. M.; Shohat, M.; Miller, D.; L[7mach[mman, R.; and Rimoin, D.
L.: [7mAch[mondroplasia with ankylosing spondylitis. Am. J. Med. Genet.
31: 117-121, 1988.
Reiser, C. A.; Pauli, R. M.; and Hall, J. G.: [7mAch[mondroplasia:
unexpected familial recurrence. Am. J. Med. Genet. 19: 245-250, 1984.
Rimoin, D. L.; Hugh.
es, G. N.; Kaufman, R. L.; Rosenthal, R. E.;
McAlister, W. H.; and Silberberg, R.: Endochondral ossification in
[7mach[mondroplastic dwarfism. New Eng. J. Med. 283: 728-735, 1970.
Siebens, A. A.; Hungerford, D. S.; and Kirby, N. A.: Curves of the
[7mach[mondroplastic spine: a new hypothesis. Johns Hopkins Med. J. 142:
Sommer, A.; Young-Wee, T.; and Frye, T.: [7mAch[mondroplasia-
hypochondroplasia complex. Am. J. Med. Genet. 26: 949-957, 1987.
Stanescu, R.; Stanescu, V.; and Maroteaux, P.: Homozygous
[7mach[mondroplasia: morphologic and biochemical study of cartilage. Am.
J. Med. Genet. 37: 412-421, 1990.
Stoll, C.; Dott, B.; Roth, M.-P.; and Alembik, Y.: Birth prevalence
rates of skeletal dysplasias. Clin. Genet. 35: 88-92, 1989.
Stoll, C.; Roth, M.-P.; and Bigel, P.: A reexamination of parental
age effect on the occurrence of new mutations for [7mach[mondroplasia. In
Papadatos, C. J. and Bartsocas, C. S. (eds.): Skeletal Dysplasias.
New York: Alan R. Liss. 1982. Pp. 419-426.
Strom, C. M.: [7mAch[mondroplasia due to DNA insertion into the type II
collagen gene. (Abstract). Pediat. Res. 18: 226A only, 1984.
Thompson, J. N., Jr.; Schaefer, G. B.; Conley, M. C.; and Mascie-
Taylor, C. G. N.: [7mAch[mondroplasia and parental age. (Letter). New Eng.
J. Med. 314: 521-522, 1986.
Velinov, M.; Slaugenhaupt, S. A.; Stoilov, I.; Scott, C. I., Jr.;
Gusella, J. F.; and Tsipouras, P.: The gene for [7mach[mondroplasia maps
to the telomeric region of chromosome 4p. Nature Genet. 6: 318-321,
Verloes, A.; Massart, B.; Jossa, V.; Langhendries, J. P.; Hainaut,
H.; Paquot, J. P.; and Koulischer, L.: Neuroblastoma in a dwarfed
newborn: possible clue to the chromosomal localization of the gene
for [7mach[mondroplasia? Ann. Genet. 34: 25-26, 1991.
Wadia, R.: [7mAch[mondroplasia in two first cousins. Birth Defects Orig.
Art. Ser. V(4): 227-230, 1969.
Wallace, D. C.; Exton, L. A.; Pritchard, D. A.; Leung, Y.; and Cooke,
R. A.: Severe [7mach[mondroplasia: demonstration of probable heterogeneity
within this clinical.
syndrome. J. Med. Genet. 7: 22-26, 1970.
Weinberg, W.: Zur Vererbung des Zwergwuchses. Arch. Rass.-u. Ges.
Biol. 9: 710-717, 1912.
Yang, S. S.; Corbett, D. P.; Brough, A. J.; Heidelberger, K. P.; and
Bernstein, J.: Upper cervical myelopathy in [7mach[mondroplasia. Am. J.
Clin. Path. 68: 68-72, 1977.
Young, I. D.; Ruggins, N. R.; Somers, J. M.; Zuccollo, J. M.; and
Rutter, N.: Lethal skeletal dysplasia owing to a double
heterozygosity for [7mach[mondroplasia and spondyloepiphyseal dysplasia
congenita. J. Med. Genet. 29: 831-833, 1992.
Growth: Short-limb dwarfism identifiable at birth.
Mean male adult height: 131 cm.
Mean female height: 124 cm.
Head: Frontal bossing.
Facies: Midfacial hypoplasia.
Low nasal bridge.
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
Joints: Limited elbow and hip extension.
Limbs: Trident hand.
Limited extension at elbows.
Neuro: Hydrocephalus occasional.
Mild hypotonia in infancy and early childhood.
Lumbar spinal stenosis common.
Occasional thoracic or cervical spinal stenosis.
Brain stem compression.
Misc: Paternal age mutation effect.
Radiology: Cuboidal vertebral bodies.
Progressive lumbar interpeduncular narrowing after first
Vertebral canal narrows in cranio-caudal direction.
Notch-like sacroiliac groove.
Circumflex or chevron seated epiphyseal ossification
centers on the metaphysis.
Short narrow femoral neck.
Wide intervertebral discs.
Flat roofed acetabula.
Small foramen magnum.
Short cranial base.
Early sphenooccipital closure.
Inheritance: Autosomal dominant with complete penetrance; most
(7/8) cases new mutations.
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
More information about the Biochrom