Meier-Gorlin syndrome: Growth and secondary sexual development of a microcephalic primordial dwarfism disorder
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 characteristics 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 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) 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 as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth. © 2012 Wiley Periodicals, Inc.
Meier–Gorlin Syndrome: Growth and Secondary
Sexual Development of a Microcephalic Primordial
Sonja A. de Munnik,
Barto J. Otten,
Louise S. Bicknell,
Jumana Y. Al-Aama,
Yolande van Bever,
Michael B. Bober,
George F. Borm,
Cheri L. Deal,
Alaa Y. Edrees,
Johanna M. van Hagen,
Raoul C. Hennekam,
Maaike C.E. Jansweijer,
Sarina G. Kant,
John M. Opitz,
A. Radha Ramadevi,
Constance T.R.M. Schrander-Stumpel,
A. Erik Sluiter,
I. Karen Temple,
Paulien A. Terhal,
Carol A. Wise,
David L. Skidmore,
Mark E. Samuels,
Lies H. Hoefsloot,
Nine V.A.M. Knoers,
Han G. Brunner,
Andrew P. Jackson,
and Ernie M.H.F. Bongers
Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen,
Department of Pediatric Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK
Northern Regional Genetics Service, Auckland Hospital, Auckland, New Zealand
Faculty of Medicine, Department of Genetic Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
Princess Al Jawhara Centre of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherla nds
Division of Genetics, Department of Pediatrics, A.I. DuPont Hospital for Children, Wilmington, Delaware
Department of Epidemiology, Biostatistics and HTA, Radboud University Nij megen Medical Centre, Nijmegen, The Netherlands
Genetic Medicine, St. Mary’s Hospital, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK
Endocrinology Service and Department of Pediatrics, Centre de Recherche du Centre Hospitalier Universitaire Ste-Justine,
e de Montr
eal, Quebec, Cana da
National Birth Defects Centre, Waltham, Massachusetts
Department of Clinical Genetics, Royal Liverpool Children’s Hospital, Liverpool, UK
Department of Clinical Genetics, VU University Medical Centre, Amsterda m, The Netherlands
Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Department of Pediatric Genetics, Emma Children’s Hospital, Academic Medical Centre, Amsterdam, The Netherlands
Shefﬁeld Clinical Genetics Service, Shefﬁeld Children’s National Health Service Foundation Trust, Shefﬁeld, UK
Department of Clinical Genetics, Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
Departments of Pediatrics (Medical Genetics), Human Genetics, Pathology, Obstetrics & Gynecology, University of Utah, Salt Lake City, Utah
Department of Clinical Genetics, Genetics Unit, Rainbow Children Hospital, Hyderabad, India
National 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 Wile y Periodicals, Inc. 2733
Department of Clinical Genetics, Ashgrove House, Aberdeen, UK
Service de G
edicale, Centre de R
erence Anomalies du D
eveloppement Centre Hospitalier R
egional Universitaire de Montpellier,
opital Arnaud de Villeneuve, Montpellier, France
Department of Clinical Genetics, and Research Institute Growth and Development (GROW), Maastricht University Medical Centre, Maastricht,
Department of Pediatrics, Ziekenhuis Bernhoven Oss-Veghel, Veghel, The Netherlands
Faculty of Medicine, Genomics and Genetic Medicine, University of Southampton, Southampton, UK
Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
Service de G
opital Bretonneau, Tours, France
Sarah M. and Charles E. Seay Centre for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas
Northern Genetics Service, Newcastle Upon Tyne Hospitals National Health Service Trust, Newcastle Upon Tyne, UK
Maritime Medical Genetics Service Izaak Walton Killam Health Centre, Halifax, Nova Scotia, Canada
Division 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, micro tia, and
patellar aplasia/hypoplasia. Recently, mutations in the ORC1,
ORC4, ORC6, CDT1, and CDC6 genes, encoding components of
the pre-r eplication 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 chara cter-
istics of MGS patients have not been reported, and so this is
addressed here through study of 45 MGS patient s, 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 (n ¼ 9) 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
as well we highlight that growth is disproportionately affected in
certain structures, with growth related minor genital abnormal-
ities (42%) and mammary hypoplasia (100%) frequently present,
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 hor mone therapy; abnormal secon dary sexual
development; genital underdevelo pment
Meier–Gorlin syndrome (MGS; ear-patella-short stature
syndrome) (OMIM#224690) is deﬁned by the triad of microtia,
patellar aplasia/hypoplasia and short stature. Other frequent ﬁnd-
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
and Jackson, 2011], characterized by severe proportionate pre- and
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; Co hen 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
with MGS described in literature [Bicknell et al., 2011a,b; Guernsey
et al., 2011]. The pre-replication complex consists of the origin
How to Cite this Article:
de Munnik SA, Otten BJ, Schoots J, Bicknell
LS, Aftimos S, Al-Aama JY, van Bever Y, Bober
MB, Borm GF, Clayton-Smith J, Deal CL,
Edrees AY, Feingold M, Fryer A, van Hag en
JM, Hennekam RC, Jansweijer MCE, Johnson
D, Kant SG, Opitz JM, Ramadevi AR, Reardon
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:
Growth and secondary sexual development of
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 comp lex 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].
Growth is globally reduced in MGS, presumably as a consequence of
mutations slowing cell proliferation, with reported mean adult
height in females of 131.6 cm (5.6 standard deviation (SD)
according to Prader et al.; range 127–148 cm, n ¼ 5), and
147.8 cm in males (3.3 SD according to Prader et al.; range
132–157.5 cm; n ¼ 3) [Prader et al., 1989; Fryns, 1998; Shalev
and Hall, 2003; Dudkiewicz and Tanzer, 2004; Guernsey et al.,
2011; Bicknell et al., 2011a]. Growth did not improve during growth
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
notably affecting the patella and ear, given that microtia and patellar
aplasia/hypoplasia are deﬁning features of MGS. Microtia can vary
profoundly, ranging from slightly small and normally positioned to
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 endocrino logical studies in
patients with MGS have not been described and no reference curves
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
overview of genital anomalies, secondary sexual characteristics, and
disrupted growth of the ears in MGS.
MATERIALS AND METHODS
Pre- and postnata l growth measurements, endocrinological ﬁnd-
ings, and data regarding development of genitalia, secondary sexual
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
of our cohort are summarized in Tables Ia and Ib. All patients were
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 gest ational age) were standardized using
the growth charts from Niklasson and Alberts son-Wikland .
Postnatal growth measurements (height, body mass index (BMI),
and head circumference for age) were standardized according to the
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
by Hall et al. . The ear morphology of 10 patients is shown in
Figure 4. A detailed description of the ear morphology of 20 patients
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. 2735
according to the terminology of Hunter et 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
not signiﬁcant, that is, when there was no indication of a non-linear
age trend, the analysis was repeated without age age. In case of
non-linearity, the relationships between age and growth during the
ﬁrst years and later years were estimated separately by in cluding the
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. Five patients were completely
excluded from analysis (three were treated with GH for an unknown
duration; of one, no measurements before the age of 47 years were
available; of one, no measurements were available after 17 weeks 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
throughout their childhood. Of six patients, only one measurement
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
Demographic data Meier–Gorlin syndrome (% or range)
Total number of patients 45
Number of females/males 28/17 (62%/38%)
Age range in years 0.3–4.7
Region of descent
Europe 21 (47%)
North America 14 (31%)
North Africa 4 (9%)
Middle East 3 (7%)
Asia 1 (2%)
Middle east/North America 1 (2%)
Oceania 1 (2%)
No known molecular cause 10 (22%)
No mutation 7
Intrauterine growth retardation 42/43 (98%)
Mean birth weight in SD
3.4 (6.5 to 0.3)
Mean birth length in SD
3.9 (13.2 to 0.0)
Mean birth head circumference in SD
2.1 (5.4 to 1.5)
Number of postpubertal/adult patients (14 F/6 M) 20 (44%)
Adult height (18 years)
Mean female height in cm (7 females) 137.7 (127.0–150.8)
Mean male height in cm (2 males) 147.0 (136.5–157.5)
Mean in SD
for both sexes 4.5 (6.4 to 2.3)
Mean female BMI (5 females) 16.8 (14.3–19.8)
Mean BMI in SD
(5 females, 1 male) 3.1 (4.9 to 0.8)
Adult head circumfere nce ( 15 years)
Mean female head circumfere nce in cm (12 females) 50.3 (45.6–53.0)
Mean male head circ umference in cm (5 males) 51.9 (44.2–57.4)
Mean in SD
for both sexes 2.4 (5.8 to þ 1.3)
SD calculated using the growth charts of Niklasson and Albertsson-Wikland .
SD calculated using growth charts of Prader et al. .
2736 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Pre- and Postnatal Growth
At birth, mean length was 3.9 SD, with a mean weight of 3.4 SD,
and mean head circumference of 2.4 SD according to Niklasson
and Albertsson-Wikland . Mean birth length was 3.5 SD
according to Prader et al. [1989 ]. In the ﬁrst year after birth, length
dropped signiﬁcant with 1.7 SD (P < 0.0001) to 5.2 SD, relative to
the general population. In other words, infants with MGS are small
at birth, but become even smaller in theﬁrstyearof life, compared to
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,
(between age 15 and 18 years) no reliable trend could be calculated.
Mean adult height (18 years of age) was 4.5 SD (females
137.7 cm, males 147.0 cm), with a BMI of 3.1 SD (females
, one male 15.0 kg/m
), and head circumference of
2.4 SD (females 50.3 cm, males 51.9 cm). Stature was proportion-
ate, except in two previously described adult females (P21 and P22)
without known molecular cause [Terhal et al., 2000]. One of these
females had a span of 136 cm and a height of 149 cm, the other had a
span of 134 cm and a height of 143.6 cm.
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-
cantly inﬂuenced by age or ethnic background compared to normal
(P > 0.05).
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
the standardized growth charts according to Prader et al. , are
illustrated in Figure 2a. In Figure 2b, the proposed reference growth
chart for height of MGS patients, derived from 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
c.266T>A p.Phe89Ser Homozygous Missense 1/1
c.314G>A p.Arg105Gln Homozygous Missense 1/1
[c.314G>A] þ [c .1482-2A>G] p.Arg105Gln þ intron
9 splice acceptor site
Heterozygous Missense þ splice site 2/2
[c.314G>A] þ [c .1999_2000delGTinsA] p.Arg105Gln þ p.Val667
X24 Heterozygous Missense þ frameshift 2/1
[c.314G>A] þ [c .1996C>T] p.Arg105Gln þ p.Arg666Trp Heterozygous Missense 1/1
[c.314G>A] þ [c .2159G>A] p.Arg105Gln þ p.Arg720Gln Heterozygous Missense 1/1
c.380A>G p.Glu127Gly Homozygous Missense 2/1
[c.1721C>T] p.Thr57Met Monoallelic Missense 1/1
c.521A>G p.Tyr174Cys Homozygous Missense 4/3
[c.521A>G] þ [c.874_875insAACA] p.Tyr174Cys þ p.Ala292
X19 Heterozygous Missense þ frames hift 2/2
[c.521A>G] þ CNV del p.Tyr174Cys þ del Heterozygous Missense þ deletion 1/1
[c.2T>C] þ [c.44 9 þ 5G>A] p.Met1? þ p.? Heterozygous Missense þ splice site 4/3
[c.257_258delTT] þ [c.695A>C] p.Phe86X þ p.Tyr232Ser Heterozygous Nonsense þ missense 3/1
[c.196G>A] þ [c.351G>C] p.Ala66Thr þ p.Gln117His
(exon 2 splicing donor site)
Heterozygous Missense þ splice site 1/1
[c.351G>C] þ [c.1385G>A] p.Gln117His (exon 2 splicing
donor site) þ p.Arg462Gln
Heterozygous Splice site þ missense 1/1
[c832G>T] þ [c.1385G>A] pGlu278X þ p.Arg462Gln Heterozygous Nonsense þ missense 2/1
[c.1081C>T] þ [c.1357C>T] p.Gln361X þ p.Arg453Trp Heterozygous Nonsense þ missense 1/1
[c.1385G>A] þ [c1560C>A] p.Arg462Gln þ p.Tyr520X Heterozygous Missense þ nonsense 4/2
[c.1385G>A] p.Arg462Gln Monoallelic Missense 2/1
c.1402G>A p.Glu468Lys Homozygous Missense 1/1
c.968C>G p.Thr323Arg Homozygous Missense 1/1
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. 2737
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
four patients and unknown in ﬁve. A positive effect of GH treatment
was seen in the two prospectively followed male patients (22%; P43
and P44, Fig. 3a,b, Table II). In both patients, height continued to
decrease, even after the infancy period, up to the age of 1.5 years, and
to standard deviations of 7 and 6.5. In both, stri kingly low IGF1
levels were detected, up to 4.6 SD, with stimulated GH levels of
11.4 and 26 mIU/L. Growth hormone treatment resulted in an
increase of height velocity in the ﬁrst year of treatment from
approximately 5 cm/year to more than 10 cm/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
(65%; 3 bilateral, 1 unilateral, 5 unknown), micropenis was present
in two out of 17 males (12%), hypospadias in one (6%). Hypoplas-
tic labia majora or minora were present in seven out of 28 females
Transvaginal ultrasound investigations were performed in 5 out
of 14 postpubertal females. A small uterus and polycystic ovaries
were observed in two females, while no abnormalities were detected
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– 5 cm. This female had two
miscarriages after 17 and 18 weeks, respectively. No fetal anomalies
were detected by ultrasound investigation and autopsy. These were
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
absent in 9 out of 12 patients (75%; 3 males, 6 females; 8 unknown),
pubic hair was sparse in 1 out of 10 patients (10%; male; 10
unknown). Mammary hypoplasia was present in all 14 postpube rtal
females. However, menarche had occurred at a normal age (before
age 14.5 years) and menstrual cycles were regular in these females.
Though endogenous ho rmonal 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 w as
observed in a third female, after treatment with 100 mg ethinyles-
tradiol between 16 and 18 years of age. In contrast, no increase in
breast size was seen in two other females treated with 20 mg
ethinylestradiol between 13.5 and 16 years of age. Hypoplastic
nipples were reported in one male, but nipples were not hypoplastic
in six postpubertal fema les (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
[c.314G>A] 1.07 N U 4.5 7.3 6.1 7.3
[c.521A>G] U N 3–1.2 3.1 7.1 10 5.3
[c.521A>G] U U U U U 15 5.5
[c.521A>G] U U U U U 15 5.8
[c.380A>G] N S U U U 4.5 5.2
[c.1385G>A] U U U 3.5 U 7.5 4.7
[c.968C>G] 0.8 U 15–12.5 2.5 4.0
[c.968C>G] 7.5 4.3 16 3.5
MU 4.6 L 11.5–10 3 6.8 14 3.0 þ
MU 3.3 N 5.3–3 5.4 5.7 7.4 3.7 þ
CA, chronological age; SA, skeletal age; GH, growth hormone; N, normal; S, suboptimal; L, low.
Patients 5 and 42 were previou sly described by Bicknell et al. [2011a] (patients 4 and 18) and Bongers et al.  (patients 1 and 3).
Patients 9 and 38 were previou sly described by Bicknell et al. [2011a] (patients 5 and 11).
Patients 10 and 11 were previously described by Bicknell et al. [2011a] (patients 6 and 7), Bongers et al. [20 01] (P5 and 6), and Guernsey et al.  (1,768 and 1,769).
Patient 27 was previously described by Bicknell et al. [2011b] (patient 1).
Patient 43 was previously described by Bongers et al.  (patient 2).
Patient 44 was not previously described.
Measurement at the age of 4 years, 1.5 years after the start of GH therapy.
2738 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Microtia (ear length < 2 SD) was present in 44 out of 45 MGS
patients (98%). The mean right ear length was 5.8 SD (20 patients,
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, pro minent 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
in patients with MGS, we show that the growth retardation in MGS
predominantly arises prenatally and in early infancy. Mean birth
length was 3.5 SD [Prader et al., 1989]. In the ﬁrst year of life,
relative length further decreased to 5.2 SD. In the following years,
growth velocity stayed normal with a height curve nearly parallel to
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
problems, present in almost all MGS patients during the ﬁrst year of
life, might contribute to the growth retardation.
Global growth, as reﬂec ted 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
efﬁcient DNA replication, of mutations in different pre-replication
complex subunits, or simply reﬂect the strength of speciﬁc muta-
tions, of which there are a limited number in each subunit so far
reported. However, the limited number of patients with a mutation
in one of the ﬁve pre-replication complex genes and the inclusion of
patients with all features of the classical triad of clinical character-
istics might have introduced ascertainment bias in these results.
Centile charts for height, weight, and head circumference cannot be
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
growth pattern during different stages of life of future patients with
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: Trends for height, body mass index, and head circumference of 33 patients with Meier–Gorlin syndrome. Growth measurements for both sexes
were standardized according to the growth charts of Prader et al. . Height dropped signiﬁcantly with 1.7 SD in the ﬁrst year after birth
(P < 0.0001) and increased with an average of 0.08 SD per year afterwards, until age 15 years (P > 0.05). Between age 15 and 18, insufﬁcient data
were available for statistical analysis. Head circumference and BMI were not signiﬁcantly inﬂuenced by age (P > 0.05). There were no differences in
growth patterns between males and females. b: Proposed growth charts for patients with Meier–Gorlin syndrome. This growth chart is based on the
trends in a cohort of 33 patients with Meier–Gorlin syndrome. Here, the growth pattern (height for age) is shown in comparison to the growth charts
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
calculate a reliable statistical trend. These data can be applied to predict height in an individual MGS patient: the growth chart of an individual patient
will differ from this chart in actual height (i.e., in distance relative to the normal growth chart), but follow the same pattern of growth velocity (i.e.,
shape) as our proposed chart.
DE MUNNIK ET AL. 2739
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
arrows represent the bone age at that age. a: Growth chart of Patient 43 (Table II; Bongers et al.  Patient 3), height improved 3.8 SD during GH
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
thereafter (Fig. 2b). The actual height of the proposed growth chart
of Figure 2b corresponds to the average heig ht of our patient group.
Corresponding curves for individual patients with different gender,
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,
such as Achondroplasia or Turner’s syndrome [Horton et al., 1978;
Park et al., 1983].
In two MGS patients, growth ho rmone treatment turned out to
be successful in improving height. Growth patterns in these patients
differed from the general pattern in our cohort, because growth
velocity continued to be reduced after early infancy and in 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 curren tly 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
suggests that IGF1 measurement s can be used to target treatment to
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)
insensitivity to estrogen as a cause of secondary sexual underdevel-
opment may be considered. This would explain the lack of response
to estrogen treatment in two patients with mammary hypoplasia.
However, the presence of normal menstrual cycles in these patients
contradicts this theory.
In the future, further prospective growth studies would be useful
to conﬁrm our results and establish more detailed growth charts, as
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-
Finally, animal studies (mouse models) might contribute to gain
insight into the embryonic development of MGS patients and
unravel pathogenic mechanisms underlying the growth retardation
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
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FIG. 4. The ear morphology of 10 patients with Meier–Gorlin syndrome. The ears are arranged from most (P38) to least underdeveloped (P18, only
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