avoided, especially in tertiary units_ Beds could be better

utilised by other antenatal patients. Growth hormone receptor

However, in smaller referral units where beds are more
readily available, patients could be managed conservatively
for up to 48 hours without increased morbidity. It has been
reported that after 48 hours of PROM the incidence of
chorio-amnionitis increases from 10% to 26.6%.12 In our
study, 76% of patients managed conservatively went into
spontaneous labour and could possibly have delivered in
peripheral units, thus further reducing the workload of the
referral hospitals_ Close observation for signs of chorio-
amnionitis is essential and vaginal examination should be
limited to patients in active labour.
The greater need for analgesics in the AMG was not
unexpected, although the overall requirement per patient
was low. Pethidine and hydroxyzine are generally available in
obstetric units and personnel are familiar with their
administration. It was reassuring to find that the active stage
was not prolonged in these patients and that the incidence
of instrumental deliveries was not increased.
The decision to induce delivery at 34 weeks' gestation was
based on the excellent prognosis of these babies in our
hospital.le. This does not necessarily reflect the situation at
other units, especially those accommodating patients from
higher socio-economic environments than our own, in whom
induction of labour should probably be postponed till 38
weeks. We recommend that management of patients with
PROM after 34 weeks should be decided upon according to
the level of antepartum and neonatal care available at the
particUlar unit. Where there is pressure on bed occupancy
and adequate neonatal support, immediate induction of
labour should be considered, while peripheral and other units
should consider conservative management before referral of
patients_ We have successfully implemented such a policy at
our obstetric units since the completion of this study.
REFERENCES
deficiency (Laron syndrome)
in black African siblings
Maxwell Hopp, ArIan L Rosenbloom, Joan Griffiths,
S. Kgwete, Mary A. Vaccarello
Non-Caucasians with growth honnone receptor (GHR)
deficiency/Lamn syndrome among the approximately 180
recognised cases are rare, and include a Japanese and 3
African Americans. Black African siblings, a brother and a
sister seen initially at 11 years 9 months and 5 years 6
months of age respectively were -7,4 and -8,0 on the
standard deviation score for height. They had
characteristic features and biochemical findings including
prominent forehead; depressed nasal bridge; central
adiposity; high-pitched voices; micropenis; high GH levels
and low levels of insulin-like growth factor (IGF)-I, IGF-II,
insulin-like growth factor-binding protein 3 (IGFBP-3), and
GH-binding protein (the solubilised extracellular domain of
the GH cell surface receptor). Molecular genetic studies
revealed a dinucleotide deletion in both siblings on exon 7
of the GHR gene, a mutation not found in any other G.HR-
deficient patient studied, including the North Americans of
African origin. Since African Americans have a substantial
admixture of Caucasian genes, n is of interest to
document the presence of this ccndnion in siblings from
Africa
S Afr Med J 1996; 86: 266-268.

1. Duff P, $ander3 R. Gibbs RS. The ~ of labour I" term palierns with chorIo·
amnionitis. Am J Obsret Gynec~ 1983; 1"7: 391-395.
2. MotaIes WJ, Laza..- AJ. Expectanl marlilgemefll of spontatIeOUS ruprure 01 the The clinical appearance of severe growth honnone (GH)
membntnes altemT. South Ued J 1986; T9; 955-958.
3. Tamsen L.. L.ymas S. Chaltil'lgUlS S. PremanJre rupWTe of the membranI!:s. deficiency, including features such as prominent forehead,
Intervenliol\ or not? GynecoI Obster Invest 1990; 29: 12&-131.
~. Conway CM. PrendiviUe WJ. Uorris Po. et aJ. Management 01 spontaneouS rupture 01
depressed nasal bridge, central adiposity and extremely
the ITleI1'lbfatlI! in the absence of ~ in primigravod women at tem'l. Am J OOsret short stature, but with elevated serum levels of GH, was first
Gyneco/ 1~; 150: ~7-951.
5. Kappy KA, CeauIo CL, KnuppeI RA. et al. Preman.w'e ruptUI'@ of the rnemCnr1es; a noted in Israel among inbred Jewish populations from Arabic
conservative appmach. Am J Obstet Gynecol 1979; 134: 655-660. countries. Forty-one patients from Israel with Laron
6. Garite TJ. Pl'emature rupture of the membranes: The emgma of the obstetrician. Am
J Obsre! Gynecd 1985; 151: 1001·1005. syndrome (LS) were eventually described including 11
1. Rovinsky JJ. Shaplro WJ. Management of premature roprure of the membtanes; 1:
Near term. Ob.ster Gynecol 1968; 32: 855-866.
Arabs. ' Sporadic cases, frequently involving siblings, have
a. Kappy KA. Cetrulo CL. Knuppel RA. er al. Premature ruptlue of the membranes at included approximately 75 additional patients from
tem'l. A comparison of j"duced and spontaneous labots. J Reprod Med 1982; 27:
29-33. predominantly Mediterranean countries and the Indian
9. Grant J, Kettse MJNC. Premature ruprure of the ~ at tenn. Irt: ChalmefS I.
Enkin MW, Ketrse MJNC. eds. A Guide to Effective c..." Pregnancy and
ChildbuTh. Oxford: Oxford Utwv~ Press. 1989: 1112-1117.
10. Uunson lA, Graham A. KOO5 BJ. et al. ts then! a need lot digital eJWIllllaDOt'l in
patients WIttl pnmature rupture of the membranes? Am J OOstet Gynecd 1985;
153: 562-563.
11. Schutte UFo Trelfers PE. KIoost.-man GJ, et aJ_ Management of pn!fTIil1UI'e Nptur8 Department of Paediatrics, Univer-sny of the Witwatersrand,
of the memoranes: The fISk of vaganaI exarnmations to !TIlt infant.. Am J 0bsTet Johannesburg
Gyneco/l983: 146: 395-400.
12. Fayu JA, HDan AA. Jonas HS. et aL Mariagem<!td of premilllUre ruptun! 01 the Maxwell Hopp, w.B. a-LB., D.c.H.., F.c.?
rnembranes.. COst!!r Gynec:oI1978; 52: 11·21.
13. van der WM D. Venter PE Management of term pregrlatlCY WIth premature ruptUre Joan Griffiths. M.B. B.CH... '-Ul~ D.c.H.
of the merrtlr3ne$ and urcfaVOUfal:lle CeMll. S AIr M#Id J 1989: 75: 54-56.
14. He$$elmg FS. Henmng PA. Kir5ten GF. ar ill. Veriengde IUplUUI van vlies& (VRVV): Department of Pediatrics, Universrty of Aorida College of Medicine,
Arltibiotikabeletd et! uitkoms '" 161 l'leOIlate by TY9erber9 Hospitaal. GeneesJtunde Gainsville. Fla. USA
1990; 32: 8·13.
15. Enklo MW, Keirse MJNC, Cl1alm4ll'$ 1. Labour and de~yery after previOuS caesarean Arian L Rosenbk>om, M.O.
section. In: EnkirI MW, KeUse MJNC, ChaImers I, eds. A Guide ro Effecw. Care in
F'regnatlCyand Cilildtwnn. Oxford:. Oxford UnlvetSlty Press. 1989: 253. Mary A. Vaccarello, M.D.
16. V3nsteertluste MAL Pattin5Ot\ RC. Kitsten GF The rrM 01 obstetric factor$ in
cietermIrwJg fetal Vlabitity. S AIr Med J 1992; 81; 5OS-5t 1. Department of Paediatrics, Ga-Rankuwa Hospital, Pretoria

AccePted 16 Jan 1995. S. Kgwete. M..B. aQi., F.C.P.

VolllM( 86 .vO. J March 1996 SAMJ

 SAMJ
ARTICLES

subcontinent. Another concentration of over 60 patients has

been found in southern Ecuador, also in an inbred
population of Spanish origin, and predominantly conversos,
i.e. Jews who became Catholic during the Inquisition.2.3 Non-
Caucasian instances have included a Japanese patient,4 and
3 unrelated African Americans. M We are unaware of any
instances of LS previously reported from Africa. 7
A defect in the GH receptor (GHR) has been recognised
as responsible for this condition since cells obtained from
liver biopsies of 2 patients failed to bind radioactive GH.!
Subsequent demonstration that the circulating high-affinity
GH-binding protein reflected the extracellular domain of the
GHR made it possible to confirm GHR abnormality without
resorting to liver biopsy.~ Localisation of the GHR gene to
chromosome 5 and characterisation of the gene permitted a
search for molecular defects in these patients.i Considerable
genetic heterogeneity has been suggested, even among
Israeli patients;lO 10 mutations have been described in the
extracellular domain of the GHR. 7 In the Ecuadorian cohort,
however, all but 1 of 46 probands studied had a nucleotide
substitution resulting in abnonnal splicing of RNA for the
GHR in an area that is preserved through all known
species."
It was of great interest to discover a brother and sister
from Africa with GHR deficiency, since the only other known
patients of African origin were from the USA, where
Caucasian gene admixture is expected.

Case report
The patients are shown in Fig. 1. They were first seen when
the boy was 11 years 9 months and the girl 5 years 6
months of age. The boy had had episodes of extreme
floppiness in the morning with non-arousability and
occasional convulsions between the ages of 2 and 8 years,
and the girl had been experiencing these since the age of
2 years. There was no known parental consanguinity. The
patients come from Sekukuniland in the Transvaal. Except
for the symptoms noted, they had been in good health.
Parents' heights were as foliows: father 172 cm, -0,7
standard deviation score (SOS) for North Americans;"
mother 153 cm (-1,8 SOS). Three unaffected sisters and an
unaffected brother were of nOtTnal stature for age. The boy
had been treated for micropenis with testosterone injections
for several months. He was an excellent student and loved
school. At age 13 years, he had a height of 95,5 cm
(-7,4 SOS, height age 3 years) and l-year growth veiocity of
4,3 cm (-2,4 SOS for bone age 8,5 years at age 12); the
girl's height at age 7 years was 77,5 cm (-8,0 SOS, height
age 1 year and 3 months) and her l-year growth rate was
2,9 cm. Weights were 100% and 94% of ideal for height,
respectively. The boy's head circumference of 50,1 cm was
normal (50th percentile) for height age and the girl's of
46,5 cm large (90th percentile) for her height age. Hand and
foot lengths were at the 50th percentiie for height. The
patients had prominent foreheads, depressed nasal bndges,
central adiposity and high-pitched voices:
Fig. 1. 11-year g-month·old brother and 5-year 6-month-old sister
with GHR deficiency (note prominent forehead, depressed nasal
bridge and central adiposity).
Biochemical studies
Biochemical studies were done at the Endocrine Sciences
Laboratories (Tarzana, California). GH levels in serum were
determined by radio-immunoassay, as were serum insulin-
like growth factor (IGF)-I and IGF-Ii concentrations, foliowing
acid chromatographic separation from their binding proteins.
Serum GH-binding protein was determined by gel filtration
of serum incubated with '25I-labelled human growth hormone
and expressed as relative specific binding (sample specific
binding divided by the specific binding of the reference adu~
male serum pool x 100). IGF binding protein 3 (IGFBP-3), the
GH-dependent binding protein accounting for 80% or more
of circulating IGF, was measured by a specific radio-
immunoassay. Results are shown in Table I. Ail vaJues were
consistent with GH resistance. 2 Random GH levels were
elevated and IGF-i unmeasurable; IFG-i1 levels were very
low. GH-binding protein activity was minimal in both
patients and the GH-dependentIGFBP-3 was also extremely
low.

SAi\1j Volume 86 No_ 3 March 1996

 Table I. Biochemical data of brother and sister with growth
hormone (GH)·receptor deficiency
Brother Sister
GH, random ()JgIl) 23;14 34
Post L-DOPA 75
GH-binding protein 1.8 5.2
(% relative specific binding)
IGF-I ()JgII) < 10 (180 - 440)" < 10 (70 - 288)"
IGF-II ()JgII) 43 (334 - 642)" 16 (334 - 642)"
IGFBP-3 ()JgII) 0.32 (2.1 - 6.2)" 0,11 (1.5 - 3.4)"
• Normal range for age in parentheses.
Molecular genetic studies
Genomic DNA from transformed leucocytes was amplified
by the polymerase chain reaction (PCR) and PCR products
encompassing the entire coding sequence and all intron-
exon boundaries of the GHR gene (except those of exon 3)
were analysed by parallel denaturing gradient gel
electrophoresis. Fragments with abnonnaJ results were
sequenced.7.ll
A dinucleotide deletion, der 230TA or AT, was found in one
sibling's GHR gene.1 The other sibling was later found to
have the same mutation. DNA was not available from the
parents to confirm homozygosity as opposed to
hemizygosity for the mutant allele.
Discussion
The clinical and biochemical phenotypes of these patients
are similar to others reported. The finding of high serum
levels of GH with low IGFBP-3 and very low IGF-I and IGF-II
levels could resutt from biologically inactive GH, or an
abnormality in the binding of GH to its cell surface receptor;
it could also resutt tram abnormaJrty in post-receptor action.
The virtual absence of GH-binding protein activity in the
circulation, however, indicates that the defect is in the GHR,
since the GH-binding protein appears to be the solubilised
extracellular domain of the GHR& The finding of a
dinucleotide deletion in exon 7 of the GHR gene affecting
transcription confirms this. The mutation was not found in
any other GHR-deficient patient studied, including 2
purportedly unrelated African American individuals who
share a single-base substitution which generates a stop
codon in exon 7 of the GHR. 7
African Americans have a substantial admixture of
Caucasian genes. It can therefore be posfulated that the
three occurrences in African Americans are evidence of
geographical drift of the same Mediterranean/southern
EuropeanlMiddle Eastem origin of all but a few of the known
instances. Such admixture is less Iikety in the patients we
are reporting and the appearance of this rare condition in
these patients is therefore of particular interest.
Consanguinity is typical in the affected populations in
Israel and Ecuador and frequently noted in sporadic isolated
or familial occurrences. Given the rarity of the GHR
deficiency and the rarity (1 instance) of compound
heterozygosity for mutations in affected subjects,7~"
unrecognised consanguinity appears likely in the few
'unrelated' parents, such as in this family.
rol'Ufto? 86 Na. J March 1996 SA.MJ
Although this article does not deal with therapeutics,
exciting developments in recombinant DNA technology have
made this condition amenable to therapy. Since this article
was originally drafted, these patients were started on IGF-1
(Igef-Kabi Pharmacia) and have responded dramatically to
this. Growth velocities have improved to well above the 97th
centile for bone age, and there has been a marked
improvement in their general well-being and appetite. The
hypoglycaemic episodes that the younger of the 2 patients
was experiencing up until the start of therapy have ceased.
Clearly, continued trials of this new therapeutic modality
will be required to establish its safety and long-term efficacy.
We thank Drs Mary Anne Berg and uta Francke of Stanford
University and Or G. Price for their assistance and EJi Ully (SA)
Lld for arranging specimen shipment.
REFERENCES
1. Lvon Z. L.aron syndt'ome: from description 10 theraIJy. EndocrJnoIot;W 1993; 3: 21~28.
2. RosenbIoom AL Guevara~AgI.JllTeJ. RosenfeId RG. F.elder PJ. The ~ women of
Loja - growth hormone-receptor ceficiency in an inbred population of 50Uthefn
EcUadOl". N EngI J Med 1990; 323; 1367-1314.
3. Guevara-Ag...arre J, Rosenbloom AL. Flelcler PJ. Oiamood Fa. Rosenleld AG. Growth
I'lormone receptor deficiency In Ecuador: clirucaJ and biochemical phenotype in two
populations. J eNn Endocrinal Metab 1993;.76: 417-423.
4. 19arashi N, Saw T. A case 01 dwarfism with severely reduced activity of growth
hormone binding protein. Nippon Nalbunpi GaAAai 2asshj 1991; 67: 121!H 229.
5. Oaughaday WH, Trivedi B. Absence 01 serum growth hormone l)inding protein in
patientS with growth honnone receptor deficiency (laron dwarfism). Proc Narl Acad
Sci 1984; 84: 4636-4640_
6. Berg MA. Argente J, Chernausek S. er al. Diverse growth hormone receptOt gene
mutations in Laron syndrome. Am J Hum Genet 1993; 52; 998~1005.
7. Rosenbloom AL Savage MO, Slum WF, Guevara-Aguine J, Rosenleld AG. Clinical
and bIomedicaJ characteristics of growth hormone receptor deficiency (Laron
syndrome). Acta Paediau Suppl1992; 383: 121-124.
8. Eshet A. Laron Z. Penzelan A. Amen R, Oinuman M. Defect of human grnwtt:I
hormone receptors in the liver of {WO patients .....ith Lawn-type dwarfism.lsr J Med
Sd 1984: 20; 8-11_
9. Amselem S. Duquesnoy P, Atuee 0, et al. t.aron dwarfism and mutations of the
growth hormone-receptor geM. N ErIgJ J ~ 1989; 321: 989-995.
10. Meac:ham LR, Brown MA, Murphy TC, et al. Detetions witi'Iin the growth honnone
receptor gene. Acra Paediau SuppJ 1992: 383: 145-149.
11. 8eo'g MA. Guevara-Aguirre J, RosenbIoom AL Aosenfeld Aa, Francke U. Mutation
creanng a new splice site in the growth hormone receptor genes of 37 Ecuadorian
patients Wl'lh Laron syndrome. Hum Muta:t 1992; 1: 24--34_
12. Nauonal Genler for Health Stanstic:s. HamiI P'VI/. NCHS growth curves for c:hikiren
blttn-18 years: Unitscl Stale$. V"1taI and health statistics. ~ 11. No. 165. (OHEW
pubUcation No. (PHS) 78- 1650). Washington. DC: Government PrInting 0tIic::e. 1977.
Accepted 17 Feb 1994.
Reprint requests to: Or M. Hopp, Private Bag 6, Bryanston, 2021.