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S110 June 2016, Vol. 106, No. 6 (Suppl 1)
THE NEW MILLENNIUM
Pyle disease is an extremely rare autosomal
recessive disorder of skeletal dysplasia, with
fewer than 30 cases reported worldwide. The
first case was reported by Pyle[1,2] in 1931, as
a case of unusual bone development. Pyle
disease is a skeletal dysplasia in which a
defect in metaphyseal remodelling leads to
distinguishing bone findings of grossly widened
metaphyses of long bones, giving Erlenmeyer-
flask bone shape. The clinical features are
usually mild genu valgum, dental caries and
malocclusion, and spinal misalignment. There
is usually no facial dysmorphism or nerve
compression, and the intelligence is normal.
Previously in South Africa (SA), four cases
of Pyle disease were reported in patients of
European ancestry, with familial history of
consanguinity in two cases[3] revealing the
autosomal recessive mode of transmission.[4]
To date, no cases have been reported
in patients with African ancestry. We
report a case of Pyle disease in a 7-year-
old African boy of mixed ancestry who
presented with finger and wrist fractures
following minor trauma, and review the
literature with particular consideration
of clinical and radiological findings of
reported cases.
Case report
A 7-year-old boy presented with fractures of
wrist and finger following minor trauma. He
was referred for assessment after radiological
findings of Erlenmeyer-flask bone deformity.
The patient was a member of a family of two
siblings; his 16-year-old sister was healthy, as
well as the two parents, and no other relevant
family history was reported (Fig. 1). There
Pyle metaphyseal dysplasia in an African child:
Case report and review of the literature
A Won ka m,1 MD, DMedSc, PhD; N Makubalo,1 MB ChB; T Roberts,2,3 BChD, MChD, PhD candidate;
M Chetty,2,3 BChD, MChD, PhD candidate
1 Division of Human Genetics, Department of Medicine, Faculty of Health Sciences University of Cape Town, South Africa
2 Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa
3 Faculty of Dentistry, University of the Western Cape, Bellville, South Africa
Corresponding author: A Wonkam (ambroise.wonkam@uct.ac.za)
Pyle disease (OMIM 265900), also known as metaphyseal dysplasia, is a rare autosomal recessive disorder with no known gene mutation. We
report a case of Pyle disease in a 7-year-old African boy of mixed ancestry who presented with finger and wrist fractures following minor
trauma. The radiological findings revealed abnormally broad metaphyses of the tubular bones, known as Erlenmeyer-flask bone deformity,
and mild cranial sclerosis, both hallmarks of the condition. We report the first case in a patient with African ancestry, which could help in
the gene discovery of this rare autosomal recessive skeletal dysplasia with unknown mutations.
S Afr Med J 2016;106(6):S110-S113. DOI:10.7196/SAMJ.2016.v106i6.11011
C
Fig. 1. e pedigree. e patient (indicated with
the arrow) was a member of a family of two
siblings; his 16-year-old sister was healthy as well
as the two parents, and no other relevant family
history was reported.
Fig. 2. Facial, dental and hand clinical phenotypes. (A, B) e patient presented with mild dysmorphic
features: prominent ears, at frontal area and mandibular prognathism. Oral examination showed the
presence of rst permanent molars plus central mandibular and maxillary incisors. (C) e remaining
teeth were all deciduous. Oral hygiene was good and apart from occasional caries, there were no notable
abnormalities. (D) e hands appeared to have normal morphology.
A B
C D
S111 June 2016, Vol. 106, No. 6 (Suppl 1)
THE NEW MILLENNIUM
was no history of consanguinity; however,
third-degree relatives came from the same
geographical area in the Western Cape.
Since the family was of mixed ancestry,
we further intensively detailed family
genealogy. Surname history did not reveal
any relationship with previously reported SA
cases[3,4] in patients of Afrikaner origin, also
from the Western Cape Province.
On clinical examination, height, weight
and head circumference were average for age.
Developmental milestones and intelligence
were normal. Facially, he presented with mild
dysmorphic features: prominent ears, flat
frontal area and mandibular prognathism
(Fig.
2A, B). Oral examination showed the
presence of first permanent molars plus
central mandibular and maxillary incisors.
No other permanent teeth were visible. The
remaining teeth were all deciduous. Oral
hygiene was good, and apart from occasional
caries there were no notable abnormalities
(Fig. 2C). The hands were both without
anomalies (Fig. 2D). Skeletal system showed
mild genu valgum and widened thickened
metaphysis of the long bones, particularly the
femora and tibiae. There was no scoliosis, no
muscle weakness and no history of joint pains.
There was no cranial nerve compression
and other systems were normal. Biological
Fig. 3. Skeletal survey revealed: (A, B) the long bones showing gross metaphyseal expansion of upper third of both femora and tibiae and the Erlenmeyer
deformity of the long bones; (C) the spine showed a generalised platyspondyly; (D) there were no notable maxillofacial or dental deformities; and (E) the skull
showed Wormian bones, thin calvarium and bossed forehead.
A B C
D E
Fig. 4. Radiographic images of parents. (A) A mild metaphyseal expansion of long bones could be described
on the mother’s radiography, suggesting heterozygocity. (B) Father’s long-bone radiography was normal.
AB
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THE NEW MILLENNIUM
Table 1. Patient description and comparative review of the literature
Countries Presentation Fracture Dysmorphism Radiological features Reference
South Africa Minor trauma + + Skull: thin cranial bones, bossing forehead, Wormian bones
Thorax: widened clavicles and ribs medially
Spine: flat vertebral bodies (platyspondyly)
Long bones: gross metaphyseal expansion of upper two-thirds of
femora and tibia
Hands: undemodelling of metacarpals
The present
case
South Africa Wrist injury + – Skull: patchy sclerosis was present in the calvarium, parasinuses and
mastoid air cells showed partial or complete pneumatisation
Thorax: clavicles flared medially, ribs widened to a lesser degree
Spine: mild dorsal scoliosis
Long bones: EFD of long bones, undertubulation of humerus in its
proximal two-thirds, undertubulation of radius and ulna in the distal two-
thirds, metacarpals undermodelled distally, healed old fractures
7
South Africa Investigated
following a
proband
– – Skull: patchy sclerosis of calvarium, poor pneumatisation of mastoid
air cells and paranasal sinuses
Chest: clavicles markedly flared medially
Pelvis: widening of ischio-pubic rami
Long bones: undertubulation of radius and ulna in the distal
two-thirds
Hands: metacarcapals 2 - 5 undermodelled distally
7
South Africa Lower back
pain
– – Skull: patchy sclerosis was present in the calvarium, prognathism was
present, paranasal sinuses and mastoid air cells showed partial or
complete pneumatisation
Thorax: flaring of the clavicle more marked medially
Spine: lumbosacral spondylosisthesis and mild platypondyly in the
dorsal spine
Long bones: undertubulation of radius and ulna in the distal two-
thirds, tibia show predominantly proximal flaring with lateral
S-shaped bowing
7
India Trivial trauma + – Skull: normal
Chest: normal
Spine: platyspondyly of dorso lumbar spine
Long bone: EFD of long bones, multiple growth arrest lines, diffuse
osteopenia and bowing of bilateral tibiae
8
India Incidental
finding in
routine dental
patient
+ – Skull: mild basal sclerosis, non-pneumatisation of frontal sinus and
partial obliteration of maxillary sinuses
Chest: widening of the medial end of both clavicles, ribs also
appeared widened with loss of corticomedullary differentiation, and
thinning cortex
Long bone: EFD of metaphyses of both femora, diapyses appeared
spaced, tibia, fibula and humerus also showed remodelling defect with
EFD, fibula appeared widened with ground-glass opacity
9
Italy Back pain +No comment Spine: platyspondyly of spine and lumbar osteoporosis with
pathological fractures
Long bones: EFD of long bones
9
Ireland Pain and
deformity of leg
+ – Skull: thickening and increased density in the base and facial region.
Absent pneumatisation of maxillary, frontal and sphenoid sinusesand
sclerosis of the petrous ridges with thickening of the posterior
clinoids. Mandible showed lack of modelling with some prognathism
Thorax: no comment
Spine: many lumbar vertebrae have collapsed with loss of normal
trabeculation, similar changes in the dorsal spine
Pelvis: showed protrusion acetabula and widening of the pubic rami
Long bone: marked thinning of cortex at the metaphysis and a
relative absence of trabeculation giving a ground- glass appearance.
Fractures of right tibia and fibula
Hands: tubula metacarpals with almost total absence of modelling.
Similar changes affect bones of forearm and humerus. A healed
fracture of the left radius
5
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THE NEW MILLENNIUM
investigations revealed normal chemistry including calcium and liver
functions and normal haematological parameters. Karyotype revealed
normal 46 XY chromosomal constitution. Skeletal survey (Fig. 3)
revealed metaphyseal expansion of the upper third of both femora and
tibiae, and the Erlenmeyer deformity of the long bones (Figs 3A,B); the
cortex of long bones was very thin with normal epiphyses (Figs
3A,B);
the spine revealed generalised platyspondyly (Fig. 3C); there were
no notable maxillofacial or dental deformities (Fig 3D) and the skull
showed Wormian bones, thin calvarium, mild cranial sclerosis and
bossed forehead (Fig. 3E). A mild metaphyseal expansion of long bones
could be described on the mother’s radiography (Fig. 4A) as well as that
of the sister. Father’s radiography was normal (Fig. 4B).
Discussion
Pyle disease is a rare autosomal recessive skeletal dysplasia without a
known causative gene. There are about 20 reported cases worldwide;
a few whose full report it was possible to obtain are presented
here (Table 1). Pyle disease is characterised by Erlenmeyer-flask
deformity (EFD), which results from defective bone modelling at the
metadiaphyseal region leading to straight, uncurved dimetaphyseal
borders and cortical thinning, giving the appearance of EFD.
The differential diagnosis for EFD includes other craniotubular
bone dysplasias such as craniometaphyseal dysplasia, craniodiaphyseal
dysplasia, Nieman-Pick disease, Gaucher disease and thalassaemia.
Pyle disease is often confused with craniometaphyseal dysplasia.[5]
In 1970, Gorlin et al.[6] described craniometaphyseal dysplasia as
a distinct entity separate from Pyle disease. Pyle disease has gross
widening of metaphyses with mild cranial sclerosis in contrast with
other craniometaphyseal dysplasias, which have severe craniofacial
or greater cranial sclerosis with mild metaphyseal changes.Despite
the remarkable radiological features of Pyle disease, the phenotypic
features are usually mild.[7] In the few reported cases of Pyle disease,
including the present case, no or mild craniofacial dysmorphism or
cranial nerve compression has been involved (Table 1).
Although the oral findings of the disease are not well documented,
several of the features that prevailed in our patient have been
previously reported.[8] The odontostomatological problems found in
patients with Pyle disease are less important than their orthopaedic
disorders, but they can stimulate the interest of the clinician to further
investigate the possibility of the presence of a bone dysplasia.[8-10]
Generally, craniofacial bones are only mildly affected. Often, an
orthopantomographic radiograph is necessary to diagnose
maxillofacial and dental deformities associated with this disorder.
In 1967, Ross and Altman[11] reviewed the literature and cited
previous literature as it related to Pyle’s work. They summarised the
clinical and radiographic findings, including maxillofacial and dental
manifestations. These included prolonged retention of deciduous
teeth, delayed eruption of permanent teeth, and numerous dental
fillings and/or other evidence of dental caries. In 2007, Narayananan
et al.[9] reported a case of an incidental finding of Pyle disease in a
routine dental patient with missing permanent teeth and retained
deciduous teeth. As patients enter their early teenage years, several
require orthodontic intervention due to a malocclusion that may develop
as a result of delayed eruption and loss of teeth due to caries.[8,9]
Comparing radiological features from other cases in the literature,
there was no significant difference in dental and other skeletal
features (Table
1).
In 1978, Raad et al.[4] reported minor degrees of undermodelling
of the distal regions of femora of obligatory and potential
heterozygotes in their patient’s family. Our patient’s sister and
mother had mild radiological features which could be subclinical
expression in the carrier gene. The father of the index patient had
no obvious radiological features (Fig. 4). Other cases of familial Pyle
disease have been reported in France,[12,13] Italy, [14,15] Portugal[16] and
Australia,[17] but surprisingly the gene involved in this condition is
not yet reported.[18]
Conclusion
We have reported the first case of Pyle disease in patients of African
ancestry. For this rare autosomal recessive skeletal dysplasia with
no known gene(s), this present case, in addition to a few others
reported worldwide, may offer an opportunity to explore the whole
genome sequences in order to identify the causative mutation. Any
gene discovery will add to better knowledge of bone remodelling
and increase insight into therapies for other bone conditions such as
osteoporosis.
Acknowledgement. Material patterned to the dental aspect of Pyle disease
and presented in the article has been featured in the PhD thesis submitted
to the University of Cape Town by Dr
M Chetty.
References
1. Faden MA, Krakow D, Ezgu F, Rimoin DL, Lachman RS. e Erlennmeyer ask deformity in the skeletal
dysplasias. Am J Med Genet A 2009;149A(6):1134-1345. DOI:10.1002/ajmg.a.32253
2. Pyle E. A case of unusual bone development. J Bone Joint Surg Am 1931;13: 874-876.
3. Beighton P. Pyle disease (metaphyseal dysplasia). J Med Genet 1987;24(6):321-324. DOI:10.1136/
jmg.24.6.321
4. Raad MS, Beighton P. Autosomal recessive inheritance of metaphyseal dysplasia (Pyle disease). Clin
Genet 1978;14(5):251-256. DOI:10.1111/j.1399-0004.1978.tb02142.x
5. Small PG, Wallis JJ. Pyle’s disease or craniometaphyseal dysplasia (tarda). Br J Radiol 1970;43(515):811-
813. DOI:10.1259/0007-1285-43-515-811.
6. Gorlin RJ, Koszalka MF, Spranger J. Pyle’s disease (familial metaphyseal dysplasia). A presentation of
two cases and argument for its separation from craniometaphyseal dysplasia. J Bone Joint Surg Am
1970;52(2):347-354.
7. Heselson NG, Raad MS, Hamersma H, Cremin BJ, Beighton P. e radiological manifestations of
metaphyseal dysplasia (Pyle disease). Br J Radiol 1979;52(618):431-440. DOI:10.1259/0007-1285-52-
618-431
8. Gupta N, Kabra M, Das CJ, Gupta AK. Pyle metaphyseal dysplasia. Indian Pediatr 2008;45(4):323-325.
9. Narayananan VS, Ashok L, Mamatha GP, Rajeshwari A, Prasad SS. Pyle’s disease: an incidental nding
in a routine dental patient. Dentomaxillofac Radiol 2006;35(1):50-54. DOI:10.1259/dmfr/44987850
10. Turra S, Gigante C, Pavanini G, Bardi C. Spinal involvement in Pyle’s disease. Pedatr Radiol
2000;30(1):25-27. DOI:10.1007/s002470050006
11. Ross MW, Altman DH. Familial metaphyseal dysplasia. Review of the clinical and radiologic feature of
Pyle’s disease. Clin Pediatr (Phila) 1967;6(3):143-149. DOI:10.1177/000992286700600309
12. Borget C, Le Bail-Darne JL, Bardin T, Bard M, Kuntz D. Pyle’s disease. Review of the literature apropos
of a case. Rev Rhum Mal Osteoartic 1991;58(4):291-294.
13. Verger P, Guichard, Puyjalon. [Pyle’s disease or familial metaphysial dysplasia (apropos of a new case)].
Pediatrie 1960;15:27-34.
14. Ferrari D, Magnani M, Donzelli O. Pyle’s disease. A description of two clinical cases and a review of the
literature. Chir Organi Mov 2005;90(3):303-307.
15. Gambardella A, Ciccarelli R, Pepe A, Mosca A. [Familial metaphyseal dysplasia (Pyle’s disease) versus
craniometaphyseal dysplasia. Presentation of a case]. Radiol Med 1990;80(3):360-363.
16. Oppenheimer C, Oliveira BC, Sogabe M, Sanvito W. [Pyle’s syndrome: report of a case]. Arq
Neuropsiquiatr 1996;54(1):120-123.
17. Vohra V. Pyle’s disease-familial metaphyseal dysplasia - a case report. Australas Radiol 1987;31(1):75-
78. DOI:10.1111/j.1440-1673.1987.tb01788.x
18. Faden MA, Krakow D, Ezgu F, Rimoin DL, Lachman RS. e Erlenmeyer ask bone deformity in the
skeletal dysplasias. Am J Med Genet 2009;149A(6):1334-1345. DOI:10.1002/ajmg.a.32253
