Meier–Gorlin Syndrome: Growth and Secondary
Sexual Development of a Microcephalic Primordial
Sonja A. de Munnik,1Barto J. Otten,2Jeroen Schoots,1Louise S. Bicknell,3Salim Aftimos,4
Jumana Y. Al-Aama,5,6Yolande van Bever,7Michael B. Bober,8George F. Borm,9Jill Clayton-Smith,10
Cheri L. Deal,11Alaa Y. Edrees,6Murray Feingold,12Alan Fryer,13Johanna M. van Hagen,14
Raoul C. Hennekam,15Maaike C.E. Jansweijer,16Diana Johnson,17Sarina G. Kant,18John M. Opitz,19
A. Radha Ramadevi,20Willie Reardon,21Alison Ross,22Pierre Sarda,23
Constance T.R.M. Schrander-Stumpel,24A. Erik Sluiter,25I. Karen Temple,26Paulien A. Terhal,27
Annick Toutain,28Carol A. Wise,29Michael Wright,30David L. Skidmore,31,32Mark E. Samuels,11
Lies H. Hoefsloot,1Nine V.A.M. Knoers,27Han G. Brunner,1Andrew P. Jackson,3
and Ernie M.H.F. Bongers1*
1Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen,
2Department of Pediatric Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
3Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK
4Northern Regional Genetics Service, Auckland Hospital, Auckland, New Zealand
5Faculty of Medicine, Department of Genetic Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
6Princess Al Jawhara Centre of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
7Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
8Division of Genetics, Department of Pediatrics, A.I. DuPont Hospital for Children, Wilmington, Delaware
9Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
10Genetic Medicine, St. Mary’s Hospital, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK
11Endocrinology Service and Department of Pediatrics, Centre de Recherche du Centre Hospitalier Universitaire Ste-Justine,
Universit? e de Montr? eal, Montr? eal, Quebec, Canada
12National Birth Defects Centre, Waltham, Massachusetts
13Department of Clinical Genetics, Royal Liverpool Children’s Hospital, Liverpool, UK
14Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands
15Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
16Department of Pediatric Genetics, Emma Children’s Hospital, Academic Medical Centre, Amsterdam, The Netherlands
17Sheffield Clinical Genetics Service, Sheffield Children’s National Health Service Foundation Trust, Sheffield, UK
18Department of Clinical Genetics, Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
19Departments of Pediatrics (Medical Genetics), Human Genetics, Pathology, Obstetrics & Gynecology, University of Utah, Salt Lake City, Utah
20Department of Clinical Genetics, Genetics Unit, Rainbow Children Hospital, Hyderabad, India
21National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Dublin, Ireland
Additional supporting information may be found in the online version of this article.
Grant sponsor: MRC and Lister Institute for Preventative Medicine.
Ernie M.H.F. Bongers, M.D., Ph.D., Department of Human Genetics 836, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB
Nijmegen, The Netherlands. E-mail: email@example.com
Article first published online in Wiley Online Library (wileyonlinelibrary.com): 28 September 2012
? 2012 Wiley Periodicals, Inc.
22Department of Clinical Genetics, Ashgrove House, Aberdeen, UK
23Service de G? en? etique M? edicale, Centre de R? ef? erence Anomalies du D? eveloppement Centre Hospitalier R? egional Universitaire de Montpellier,
H^ opital Arnaud de Villeneuve, Montpellier, France
24DepartmentofClinicalGenetics, andResearchInstitute GrowthandDevelopment(GROW),Maastricht UniversityMedical Centre,Maastricht,
25Department of Pediatrics, Ziekenhuis Bernhoven Oss-Veghel, Veghel, The Netherlands
26Faculty of Medicine, Genomics and Genetic Medicine, University of Southampton, Southampton, UK
27Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
28Service de G? en? etique, H^ opital Bretonneau, Tours, France
29Sarah M. and Charles E. Seay Centre for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas
30Northern Genetics Service, Newcastle Upon Tyne Hospitals National Health Service Trust, Newcastle Upon Tyne, UK
31Maritime Medical Genetics Service Izaak Walton Killam Health Centre, Halifax, Nova Scotia, Canada
32Division of Medical Genetics, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
Manuscript Received: 30 November 2011; Manuscript Accepted: 3 September 2012
Meier–Gorlin syndrome (MGS) is a rare autosomal recessive
disorder characterized by primordial dwarfism, microtia, and
patellar aplasia/hypoplasia. Recently, mutations in the ORC1,
ORC4, ORC6, CDT1, and CDC6 genes, encoding components of
the pre-replication complex, have been identified. This complex
is essential for DNA replication and therefore mutations are
expected to impair cell proliferation and consequently could
globally reduce growth. However, detailed growth character-
istics of MGS patients have not been reported, and so this is
addressed here through study of 45 MGS patients, the largest
cohort worldwide. Here, we report that growth velocity (length)
is impaired in MGS during pregnancy and first year of life, but,
thereafter, height increases in paralleled normal reference
centiles, resulting in a mean adult height of ?4.5 standard
deviations (SD). Height is dependent on ethnic background
and underlying molecular cause, with ORC1 and ORC4 muta-
tions causing more severe short stature and microcephaly.
Growth hormone therapy (n¼9) was generally ineffective,
though in two patients with significantly reduced IGF1 levels,
growth was substantially improved by GH treatment, with 2SD
and 3.8 SD improvement in height. Growth parameters for
monitoring growth in future MGS patients are provided and
certain structures, with growth related minor genital abnormal-
in addition to established effects on ears and patellar growth.
? 2012 Wiley Periodicals, Inc.
Key words: Meier–Gorlin syndrome; ear-patella-short stature;
growth; growth hormone therapy; abnormal secondary sexual
development; genital underdevelopment
syndrome) (OMIM#224690) is defined by the triad of microtia,
patellar aplasia/hypoplasia and short stature. Other frequent find-
syndrome (MGS;ear-patella-short stature
ings include pulmonary emphysema and typical facial character-
istics (Fig. 1). MGS is part of a group of autosomal recessive
disorders called microcephalic primordial dwarfism [Klingseisen
postnatal growth deficiency, and microcephaly.
Sixty-three cases of MGS have been described in literature, thus
far [Meier et al., 1959; Gorlin et al., 1975; Hurst et al., 1988; Cohen
et al., 1991; Boles et al., 1994; Lacombe et al., 1994; Buebel et al.,
1996; Fryns, 1998; Loeys et al., 1999; Verhallen et al., 1999; Terhal
et al., 2000; Bongers et al., 2001; Cohen et al., 2002; Feingold,
2002; Shalev and Hall, 2003; Dudkiewicz and Tanzer, 2004; Faqeih
et al., 2005; Gezdirici et al., 2010; Guernsey et al., 2011; Bicknell
et al., 2011a,b; de Munnik et al., 2012]. Recently, mutations in five
different pre-replication complex genes (ORC1, ORC4, ORC6,
CDT1, and CDC6) were identified in 67% (31/46) of patients
et al., 2011]. The pre-replication complex consists of the origin
How to Cite this Article:
de Munnik SA, Otten BJ, Schoots J, Bicknell
MB, Borm GF, Clayton-Smith J, Deal CL,
Edrees AY, Feingold M, Fryer A, van Hagen
W, Ross A, Sarda P, Schrander-Stumpel
CTRM, Sluiter AE, Temple IK, Terhal PA,
Toutain A, Wise CA, Wright M, Skidmore
DL, Samuels ME, Hoefsloot LH, Knoers
NVAM, Brunner HG, Jackson AP, Bongers
EMHF. 2012. Meier–Gorlin syndrome:
a microcephalic primordial dwarfism
Am J Med Genet Part A 158A:2733–2742.
2734 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
recognition complex (subunits ORC1–ORC6), two regulatory
proteins (CDT1 and CDC6), and the MCM helicase complex.
The complex forms at origins of DNA replication and is essential
for initiation of genome replication, a crucial step in cell cycle and
cellular growth [Bell and Stillman, 1992; Nishitani et al., 2000].
mutations slowing cell proliferation, with reported mean adult
height in females of 131.6cm (?5.6 standard deviation (SD)
according to Prader et al.; range 127–148cm, n¼5), and
147.8cm in males (?3.3 SD according to Prader et al.; range
132–157.5cm; n¼3) [Prader et al., 1989; Fryns, 1998; Shalev
and Hall, 2003; Dudkiewicz and Tanzer, 2004; Guernsey et al.,
hormone (GH) therapy performed in six patients, thus far
[Lacombe et al., 1994; Cohen et al., 2002; Faqeih et al., 2005;
Guernsey et al., 2011; Bicknell et al., 2011b].
Reductions in growth of specific tissues are also evident, most
aplasia/hypoplasia are defining features of MGS. Microtia can vary
abnormally shaped and positioned ears. Only one patient was
reported to have normal sized and shaped ears [Bicknell et al.,
2011b]. Additionally, genital growth may be specifically affected
both evident at birth, resulting in minor genital anomalies, and
during secondary sexual development, resulting in mammary
hypoplasia [Gorlin et al., 1975; Lacombe et al., 1994; Buebel
et al., 1996; Loeys et al., 1999; Terhal et al., 2000; Bongers et al.,
2001; Shalev and Hall, 2003; Guernsey et al., 2011; Bicknell et al.,
Detailed longitudinal growth and endocrinological studies in
for height, weight, and head circumference have been established.
Here, we provide an overview of growth in a unique cohort of 45
MGS patients, the largest worldwide. Moreover, we describe the
beneficial effect of GH treatment in two MGS patients with
additional growth hormone insufficiency. Finally, we provide an
disrupted growth of the ears in MGS.
MATERIALS AND METHODS
Pre- and postnatal growth measurements, endocrinological find-
characteristics, and ears of 45 patients with MGS were collected
retrospectively by sending clinical questionnaires to the referring
physicians and prospectively by physical examination and labora-
tory investigations. The cohort comprised 28 females (62%) and
17 males (38%), aged between 3 months and 47 years. Twenty
patients had reached postpubertal or adult age (44%; 6 males,
14 females). Gynecologic examination, including a transvaginal
ultrasound, was performed in five females. The demographic data
previously described in literature [Gorlin et al., 1975; Cohen et al.,
1991; Lacombe et al., 1994; Verhallen et al., 1999; Terhal et al.,
2000; Bongers et al., 2001; Feingold, 2002; Shalev and Hall, 2003;
Guernsey et al., 2011; Bicknell et al., 2011a,b; de Munnik et al.,
Anthropometric measurements at birth (length, weight, and
head circumference for gestational age) were standardized using
Postnatal growth measurements (height, body mass index (BMI),
growth charts from Prader et al. , as used by Ranke et al.
 in their international evaluation of growth and growth
Endocrinological data (IGF1, stimulated GH, LH, FSH, estro-
gen, and testosterone levels) of 15 patients were available and
standardized according to Rikken et al. . GH treatment
was initiated in nine patients. Two of these patients (P43 and
P44, Table II) were prospectively followed, seven were retrospec-
In addition to a short stature and small head circumference,
microtia is one of the most characteristic features of MGS. The ear
length of 20 patients was compared to the normal values provided
FIG. 1. Facial characteristics of three patients with Meier–Gorlin syndrome. Note the characteristic face with small, abnormally shaped ears,
beaked nose, small mouth with full lips, and retrognathia. Patient 13 was previously described by Lacombe et al.  and Bicknell et al.
[2011a] (Case 3 and Patient 8, respectively). Patients 20 and 43 were previously described by Bongers et al.  (patients 4 and 2,
DE MUNNIK ET AL.
according to the terminology of Hunteret al. is provided in
Supplementary eTable I.
A linear mixed model with random factor patient was used to
analyze the standardized height and head circumference according
to Prader et al. (random intercept model) [Leyland and Goldstein,
2001; Prader et al., 1989]. Independent fixed factors were sex,
molecular cause, and region of descent. Age and age?age were
included as fixed covariates. When the coefficient of age?age was
age trend, the analysis was repeated without age?age. In case of
variables age- and max (0, age-1; the latter variable represents the
difference between the growth in the first year and second year).
Growth data after the age of 20 years or after start of GH treatment
were excluded from growth analysis. Fivepatients were completely
duration; of one, no measurements before the age of 47 years were
available; ofone,no measurements wereavailable after 17weeks of
gestation). Six patients were excluded from growth analysis
after GH treatment was initiated. Four hundred fifty two measure-
ments of 40 patients were obtained on different ages from birth
was available. Of 19 patients, five or more measurements were
TABLE Ia. Demographic Data and Data on Growth and Sexual Development of a Cohort of 45 Patients With Meier–Gorlin Syndrome
Total number of patients
Number of females/males
Age range in years
Region of descent
Middle east/North America
No known molecular cause
Monoallelic mutation ORC1
Monoallelic mutation CDT1
Intrauterine growth retardation
Mean birth weight in SD1
Mean birth length in SD1
Mean birth head circumference in SD1
Number of postpubertal/adult patients (14 F/6 M)
Adult height (?18 years)
Mean female height in cm (7 females)
Mean male height in cm (2 males)
Mean in SD2for both sexes
Mean female BMI (5 females)
Mean BMI in SD2(5 females, 1 male)
Adult head circumference (?15 years)
Mean female head circumference in cm (12 females)
Mean male head circumference in cm (5 males)
Mean in SD2for both sexes
(% or range)
(?6.5 to ?0.3)
(?13.2 to 0.0)
(?5.4 to 1.5)
(?6.4 to ?2.3)
(?4.9 to ?0.8)
(?5.8 to þ1.3)
1SD calculated using the growth charts of Niklasson and Albertsson-Wikland .
2SD calculated using growth charts of Prader et al. .
2736AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Pre- and Postnatal Growth
and mean head circumference of ?2.4 SD according to Niklasson
and Albertsson-Wikland . Mean birth length was ?3.5 SD
accordingto Prader etal. .Inthe first year after birth, length
the general population. Thereafter, height remained below, but
increased in parallel with the population centiles (nonsignificant
gain of 0.08 SD/year, until age 15 years (P>0.05)). Afterwards,
Mean adult height (?18 years of age) was ?4.5 SD (females
137.7cm, males 147.0cm), with a BMI of ?3.1 SD (females
16.8kg/m2, one male 15.0kg/m2), and head circumference of
without known molecular cause [Terhal et al., 2000]. One of these
span of 134cm and a height of 143.6cm.
Height appeared to be significantly affected by ethnic origin
(P<0.0001): patients from the Middle East were shortest,
followed by patients from North America, Europe, and North
Africa. In contrast, BMI and head circumference were not signifi-
Height and head circumference were significantly influenced by
the underlying molecular cause (P<0.0001). Patients with muta-
tions in ORC1 or ORC4 had a significantly shorter stature and
smaller head circumference than patients with mutations in other
genes (ORC6, CDT1, CDC6, or unknown genes), such that they
were 4.7 SD (ORC1) and 3.1 SD (ORC4) shorter than the others
(after adjustment for ethnic origin). For head circumference, the
differences were 5.0 SD and 1.6 SD, respectively.
Prenatal and postnatal growth data are summarized in Table Ia.
The trends for height, BMI, and head circumference for age, using
chartfor height of MGSpatients,derivedfrom this data analysis, is
shown. The difference between the reference growth curve and the
normal curve corresponds to the average difference for our patient
population. For individual patients the difference may depend on
ethnic background, gender, and mutated gene. However, the slope
of the curve (growth velocity) is independent of these factors.
Growth Hormone Levels and Growth Hormone
GH status, assessed by IGF1 and/or stimulated GH measurements,
was normal in 12 out of 15 (80%) patients tested. Low IGF1 levels
TABLE Ib. Overview of Mutations Identified in a Cohort of 45 Patients With Meier–Gorlin Syndrome
Gene Nucleotide alterations
9 splice acceptor site
(exon 2 splicing donor site)
p.Gln117His (exon 2 splicing
Biallelic mutations were found in 35 patients, monoallelic mutations in three patients. In seven patients, no mutations were detected.
Adapted from de Munnik et al. .
DE MUNNIK ET AL.
were detected in one female (?2.3 SD; P21) and two males (?4.6
and ?3.3; P43 and P44, respectively, described below). The female
was never treated with growth hormone.
GH therapy was initiated in 9 out of 45 patients (20%). An
overview of their GH status, skeletal age, the period of GH treat-
ment, and effect on height is presented in Table II. GH status was
normal in seven patients, but abnormal in two (P43 and P44).
Skeletal age according to Greulich and Pyle  was delayed in
and P44, Fig. 3a,b, Table II). In both patients, height continued to
levels were detected, up to ?4.6 SD, with stimulated GH levels of
11.4 and 26mIU/L. Growth hormone treatment resulted in an
increase of height velocity in the first year of treatment from
approximately 5cm/year to more than 10cm/year, with a total
gain of 2 SD and 3.8 SD within 2 years after the start of treatment,
Abnormalities of Genital and Secondary Sexual
Minor anomalies of external genitalia were present in 19 out of 45
patients (42%). Cryptorchidism was seen in 11 out of 17 males
tic labia majora or minora were present in seven out of 28 females
Transvaginal ultrasound investigations wereperformed in 5out
of 14 postpubertal females. A small uterus and polycystic ovaries
in two others. In the fifth female (P22), ultrasound investigations,
which were performed after premature delivery, showed a short-
ened uterus with a probe length of 4–5cm. This female had two
the first two pregnancies in a patient with MGS.
Secondary sexual development was affected in 17 out of 20
patients (85%, males and females). Axillary hair was sparse or
pubic hair was sparse in 1 out of 10 patients (10%; male; 10
females. However, menarche had occurred at a normal age (before
age 14.5 years) and menstrual cycles were regular in these females.
Though endogenous hormonal levels were normal, exogenous
estrogen treatment was initiated in five females. An increase in
breast size was reported in two females. A very mild increase was
observed in a third female, after treatment with 100mg ethinyles-
tradiol between 16 and 18 years of age. In contrast, no increase in
breast size was seen in two other females treated with 20mg
ethinylestradiol between 13.5 and 16 years of age. Hypoplastic
in six postpubertal females (unknown in the other eight females).
TABLE II. Growth Hormone Levels and the Effect of Growth Hormone Treatment in Nine Patients With Meier–Gorlin Syndrome
F ORC4UUUUU 15
F ORC4UUUUU 15
M ORC1NSUUU 4.5
M CDT1UUU 3.5U 7.5
CA, chronological age; SA, skeletal age; GH, growth hormone; N, normal; S, suboptimal; L, low.
1Patients 5 and 42 were previously described by Bicknell et al. [2011a] (patients 4 and 18) and Bongers et al.  (patients 1 and 3).
2Patients 9 and 38 were previously described by Bicknell et al. [2011a] (patients 5 and 11).
3Patients 10 and 11 were previously described by Bicknell et al. [2011a] (patients 6 and 7), Bongers et al.  (P5 and 6), and Guernsey et al.  (1,768 and 1,769).
4Patient 27 was previously described by Bicknell et al. [2011b] (patient 1).
5Patient 43 was previously described by Bongers et al.  (patient 2).
6Patient 44 was not previously described.
7Measurement at the age of 4 years, 1.5 years after the start of GH therapy.
2738AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Microtia (ear length<?2 SD) was present in 44 out of 45 MGS
range ?7.3 to ?3.1 SD), the mean left ear length ?5.3 SD (20
patients, range ?7.9 to ?3.2 SD). Most ears were small, with a
shelved antihelix, prominent crus, and small or absent ears lobes.
The ear anomalies of 10 MGS patients are shown in Figure 4. A
detailed description according to the morphology of Hunter et al.
 of the ear malformations of 20 patients is provided in
Supplementary eTable I.
In this first retrospective and partially prospective study of growth
predominantly arises prenatally and in early infancy. Mean birth
length was ?3.5 SD [Prader et al., 1989]. In the first year of life,
normal and a mean adult height of ?4.5 SD. This pattern is
consistent with an intrinsic growth problem of reduced cellular
proliferation, though, surprisingly, growth velocity post infancy is
not perturbed. Alternatively, placental dysfunction could poten-
tially cause growth impairment in MGS prenatally, while feeding
life, might contribute to the growth retardation.
Global growth, as reflected by both height and head circumfer-
ence, was influenced by the underlying molecular cause: ORC1
mutations caused the most severe growth retardation, followed by
ORC4 mutations. This might represent a differential sensitivity to
complex subunits, or simply reflect the strength of specific muta-
tions, of which there are a limited number in each subunit so far
patients with all features of the classical triad of clinical character-
istics might have introduced ascertainment bias in these results.
established given the rarity of this condition, the restricted size of
our cohort and the lack of measurements at standardized ages.
Our data have clinical utility and will be useful in predicting the
MGS. Our data can be used to predict the height of a patient, since
height decreases with 1.7 SD during the first year of life and the
growth velocity is nearly equal to the normal growth velocity
FIG. 2. a:Trendsforheight,bodymassindex,andheadcircumferenceof33patientswithMeier–Gorlinsyndrome.Growthmeasurementsforbothsexes
were standardized according to the growth charts of Prader et al. . Height dropped significantly with 1.7 SD in the first year after birth
for boys of Prader et al. . This growth pattern is the same for males and females. After 15 years of age, insufficient data were available to
willdifferfrom thischartinactualheight(i.e.,indistance relativeto thenormalgrowth chart),butfollowthe samepattern ofgrowth velocity(i.e.,
shape) as our proposed chart.
DE MUNNIK ET AL.
FIG. 3. a,b: Growth charts of two patients with Meier–Gorlin syndrome showing a positive response to growth hormone treatment. Height for age is
compared to the growth charts of Prader et al. . The green highlighted areas represent the period of GH treatment. The black/gray dots and
therapy. b: Growth chart of Patient 44 (Table II; de Munnik et al.  individual i) height improved 2 SD during GH therapy.
2740 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
ethnic background, or mutated gene, would lie closer to or
further away from the normal curve according to Prader et al.
, but the growth velocity is independent of these factors, so
they would all run parallel to our proposed growth chart of
Figure 2b. This is in contrast to growth curves in other syndromes,
Park et al., 1983].
In two MGS patients, growth hormone treatment turned out to
differed from the general pattern in our cohort, because growth
velocity continued tobereducedafter earlyinfancyandin particu-
lar, extremely low IGF1 levels were found (Table II). Notably
though, these two patients had a classic MGS phenotype with
microtia and patellar aplasia and the underlying molecular cause
is currently unknown for both of them. It is tempting to speculate
that the gene causing MGS in these two patients might play an
important role in the growth hormone axis. Furthermore, this
a subset of MGS patients that will respond to GH therapy, in
contrast to those with mutations in the pre-replication complex,
who appear unlikely to benefit from GH therapy.
Mammary hypoplasia was present in all postpubertal females.
Besides an early disturbance of embryonic development, (partial)
insensitivityto estrogen asa cause ofsecondary sexual underdevel-
to estrogen treatment in two patients with mammary hypoplasia.
contradicts this theory.
well as more systematically assessing the effect of GH treatment in
MGS patients. Further studies of an increased number of MGS
patients with a known molecular cause and elucidation of the
genetic defect in MGS patients with a yet unknown molecular
cause will further define the phenotypic spectrum of MGS, includ-
insight into the embryonic development of MGS patients and
and underdevelopment of genitalia, secondary sexual character-
istics, and ears in MGS.
The authors would like to thank the patients and their parents.
A.P.J. is funded by the MRC and Lister Institute for Preventative
of DNA replication by a multiprotein complex. Nature 357:128–134.
Bicknell LS, Bongers EMHF, Leitch A, Brown S, Schoots J, Harley ME,
Aftimos S, Al-Aama JY, Bober M, Brown PAJ, van Bokhoven H, Dean J,
Edrees AY, Feingold M, Fryer A, Hoefsloot LH, Kau N, Knoers NVAM,
cause Meier–Gorlin syndrome. Nat Genet 43:356–359.
FIG. 4. The ear morphology of 10 patients with Meier–Gorlin syndrome. The ears are arranged from most (P38) to least underdeveloped (P18, only
previously described by de Munnik et al.  (individual i).
DE MUNNIK ET AL.
Bicknell LS, Walker S, Klingseisen A, Stiff T, Leitch A, Kerzendorfer C, Download full-text
AP, O’Driscoll M, Jeggo PA. 2011b. Mutations in ORC1, encoding the
largest subunit of the origin recognition complex, cause microcephalic
primordial dwarfism resembling Meier–Gorlin syndrome. Nat Genet
ear, patella, short stature syndrome (Meier–Gorlin syndrome). Clin
Bongers EM, Opitz JM, Fryer A, Sarda P, Hennekam RC, Hall BD,
Superneau DW, Harbison M, Poss A, van Bokhoven H, Hamel BCJ,
Knoers NVAM. 2001. Meier–Gorlin syndrome: Report of eight addi-
tional cases and review. Am J Med Genet 102:115–124.
1996. A new Seckel-like syndrome of primordial dwarfism. Am J Med
Cohen B, Temple IK, Symons JC, Hall CM, Shaw DG, Bhamra M, Jackson
AM, Pembrey ME. 1991. Microtia and short stature: A new syndrome.
J Med Genet 28:786–790.
Cohen A, Mulas R, Seri M, Gaiero A, Fichera G, Marini M, Baffico M,
Camera G. 2002. Meier–Gorlin syndrome (ear-patella-short stature
syndrome) in an Italian patient: clinical evaluation and analysis of
possible candidate genes. Am J Med Genet 107:48–51.
Clayton-Smith J, Edrees AY, Feingold M, Fryer A, van Hagen JM,
AR, Reardon W, Ross A, Sarda P, Schrander-Stumpel CT, Schoots J,
Temple IK, Terhal PA, Toutain A, Wise CA, Wright M, Skidmore DL,
Samuels ME, Hoefsloot LH, Knoers NV, Brunner HG, Jackson AP,
Bongers EM. 2012. Meier–Gorlin syndrome genotype-phenotype
studies: 35 Individuals with pre-replication complex gene mutations
and 10 without molecular diagnosis. Eur J Hum Genet 20:598–606.
Dudkiewicz M, Tanzer M. 2004. Total knee arthroplasty in Meier–Gorlin
syndrome. J Arthroplasty 19:931–934.
Faqeih E, Sakati N, Teebi AS. 2005. Meier–Gorlin (ear-patella-short
stature) syndrome: Growth hormone deficiency and previously unrec-
ognized findings. Am J Med Genet Part A 137A:339–341.
Feingold M. 2002. Meier–Gorlin syndrome. Am J Med Genet 109:338.
Fryns JP. 1998. Meier–Gorlin syndrome: The adult phenotype. Clin
Gezdirici A, Yosunkaya E, Paydas A, Seven M, Yuksel A. 2010. Expanding
the phenotypical spectrum of Meier–Gorlin syndrome with novel find-
Gorlin RJ, Cervenka J, Moller K, Horrobin M, Witkop CJ Jr. 1975.
Greulich WW, Pyle SL. 1959. Radiographic atlas of skeletal development
of the hand and wrist, 2nd edition. Stanford:
Guernsey DL, Matsuoka M, Jiang H, Evans S, Macgillivray C, Nightingale
M, Perry S, Ferguson M, Leblanc M, Paquette J, Patry L, Rideout AL,
Thomas A, Orr A, McMaster CR, Michaud JL, Deal C, Langlois S,
Superneau DW, Parkash S, Ludman M, Skidmore DL, Samuels ME.
2011. Mutations in origin recognition complex gene ORC4 cause
Meier–Gorlin syndrome. Nat Genet 43:360–364.
Hall JG, Allanson JE, Gripp KW. Slavotinek AM. 2007. Handbook of
Horton WA, Rotter JI, Rimoin DL, Scott CI, Hall JG. 1978. Standard
growth curves for achondroplasia. J Pediatr 93:435–438.
Hunter A, Frias JL, Gillessen-Kaesbach G, Hughes H, Jones KL, Wilson L.
2009. Elements of morphology: Standard terminology for the ear. Am J
Med Genet Part A 149A:40–60.
Hurst JA, Winter RM, Baraitser M. 1988. Distinctive syndrome of short
stature, craniosynostosis, skeletal changes, and malformed ears. Am J
Med Genet 29:107–115.
Klingseisen A, Jackson AP. 2011. Mechanisms and pathways of growth
failure in primordial dwarfism. Genes Dev 25:2011–2024.
Lacombe D, Toutain A, Gorlin RJ, Oley CA, Battin J. 1994. Clinical
identification of a human equivalent to the short ear (se) murine
phenotype. Ann Genet 37:184–191.
Leyland AH, Goldstein H. 2001. Multilevel health modeling of statistics.
Chichester: Wiley Europe. p 246.
Lindberg A, Ranke MB. 2007. Data analysis in KIGS. In: Ranke MB, Price
of KIGS. Basel: Karger. pp 23–28.
Loeys BL, Lemmerling MM, Van Mol CE, Leroy JG. 1999. The
Meier–Gorlin syndrome, or ear-patella short stature syndrome, in
sibs. Am J Med Genet 84:61–67.
congenita with mandibulofacial dysostosis (Franceschetti syndrome).
Helv Paediatr Acta 14:213–216.
Niklasson A, Albertsson-Wikland K. 2008. Continuous growth reference
from 24th week of gestation to 24 months by gender. BMC Pediatr 8:8.
Nishitani H, Lygerou Z, Nishimoto T, Nurse P. 2000. The Cdt1 protein is
required to license DNA for replication in fission yeast. Nature
Turner’s syndrome. Pediatr Res 17:1–7.
Prader A, Largo RH, Molinari L, Issler C. 1989. Physical growth of Swiss
children from birth to 20 years of age. First Zurich longitudinal study of
growth and development. Helv Paediatr Acta Suppl 52:1–125.
RikkenB,vanDoornJ,RingelingA,Vanden Brande JL,MassaG, WitJM.
1998. Plasma levels of insulin-like growth factor (IGF)-I, IGF-II and
IGF-binding protein-3 in the evaluation of childhood growth hormone
deficiency. Horm Res 50:166–176.
Shalev SA, Hall JG. 2003. Another adult with Meier–Gorlin syndrome—
insights into the natural history. Clin Dysmorphol 12:167–169.
GMC. 2000. Breast hypoplasia and disproportionate short stature in the
ear, patella, short stature syndrome: Expansion of the phenotype? J Med
Verhallen JCTM, van der Lely N, Kant SG. 1999. Het syndroom van
Meier–Gorlin. Tijdschr Kindergeneesk 67:32–35.
2742 AMERICAN JOURNAL OF MEDICAL GENETICS PART A