Clinical and endocrine characteristics in atypical and classical growth hormone insensitivity syndrome.
OBJECTIVE
Classical growth hormone insensitivity syndrome (GHIS) comprises a dysmorphic phenotype, extreme short stature (height SDS < 3), normal GH and low IGF-I and IGFBP-3. Wide clinical variation is recognised with classical and atypical forms. We aimed to delineate features of the milder "atypical" GHIS phenotype, and to determine whether this correlates with milder auxological and biochemical features.


METHODS
Fifty-nine patients from a European series of 82 patients with GHIS, with strict diagnostic criteria of GHIS, were studied and assigned to classical or atypical GHIS groups according to facial phenotype, i.e. "classical" required 2 of 3 recognized GHIS features (frontal bossing, mid-facial hypoplasia and depressed nasal bridge), "atypical" required 0 or 1 of these facial features. Classical and atypical GHIS groups were compared in terms of (1) phenotypic features, including high-pitched voice, sparse hair, blue sclera, hypoglycaemia, microphallus, (2) birth length, height SDS, and (3) basal IGF-I, IGF-II, IGFBP-1, IGFBP-3, GHBP and increase in IGF-I on IGF-I generation testing.


RESULTS
Fifty patients [24 males, 26 females, aged 8.6 +/- 4.6 years (mean +/- SD)] had "classical GHIS", 9 patients (7 males, 2 females, aged 7.8 +/- 4.1 years) had "atypical GHIS", 7 with normal facies. Atypical GHIS patients had lesser height deficit (Ht SDS -4.0 +/- 1.4) compared to classical GHIS (-6.7 +/- 1.4), less reduction in IGFBP-3 SDS (atypical -5.5 +/- 3.3; classical -8.6 +/- 2.4), and more had normal GHBP (>10% binding). Other variables were also less frequent in atypical GHIS patients: high-pitched voice 11% (70% classical), sparse hair 11% (42% classical), blue sclera 0% (38% classical), hypoglycaemia 11% (42% classical), and microphallus 14% (1 of 7 males), compared to 79% of classical (19 of 24 males).


CONCLUSIONS
Atypical GHIS patients, with relatively normal facial appearance, demonstrate less height defect and biochemical abnormalities compared to classical patients. GH insensitivity may be present in children with short stature and an otherwise normal appearance.
Burren
C P
CP
Paediatric Section, Dept. of Endocrinology, St. Bartholomew's Hospital, London EC1A 7BE, UK.
Woods
K A
KA
Rose
S J
SJ
Tauber
M
M
Price
D A
DA
Heinrich
U
U
Gilli
G
G
Razzaghy-Azar
M
M
Al-Ashwal
A
A
Crock
P A
PA
Rochiccioli
P
P
Yordam
N
N
Ranke
M B
MB
Chatelain
P G
PG
Preece
M A
MA
Rosenfeld
R G
RG
Savage
M O
MO
D001827:Body Height; D002648:Child; D005260:Female; D006130:Growth Disorders / Q000145:classification* / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D019382:Human Growth Hormone / Q000097:blood / Q000378:metabolism*; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D010641:Phenotype; D013577:Syndrome
D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I