We report a 3.8 years old girl who was referred to our Pediatric Endocrinology Department for short stature. At first evaluation she was 1.6 years old. She presented a symmetrical short stature: height was 72.5 cm (−2.58 SDS), sitting height was 46.1 cm (−2.3 SDS), sitting height/height ratio was 0.63 (0 SDS), weight was 8.2 kg (−3.15 SDS) and head circumference was 46.8 cm (+0.31 SDS). She was prepuberal. Facial features included frontal bossing and depressed nasal bridge. No other congenital abnormalities were evident (Fig. 1). Subscapular skinfold was 18.4 mm, tricipital skinfold 12.5 mm.
She was born from a pregnancy of 36 + 5 weeks characterized by gestational mellitus diabetes. Neonatal weight was 2900 g (AGA), length was 47.7 cm (AGA), head circumference was 33 cm (AGA) and Apgar score was 9/10. During the second day of birth, she developed severe hypoglycaemia that required glucose infusion. Her father and mother are not related, with proportional and normal height: mother height is 162 cm whereas father height is 180 cm (target height 164.5 cm). There are no cases of short stature in family members (only child). Parents’ origin was from North of Italy and Sicily.
Biochemically, blood count, creatinine, liver function, electrolytes, urine evaluation and serological screening for celiac disease were normal. Her serum basal GH levels were 11.57 ng/ml with glucose levels of 59 mg/dl, IGF-1 19.1 ng/ml (−2.7 SDS) and IGFBP-3 0.7 mcg/ml (2.0–4.5), respectively.
We failed to detect a positive response to the standard IGF-1 generation test by administering 0.033 mg/kg/day of rhGH for 4 consecutive days [IGF-1 d0: 13.6 ng/ml (−2.6 SDS); IGF-1 d4: 8.4 ng/ml (−2.8 SDS)], indicating a GH resistance.
Auxological follow-up for height is shown in Fig. 2.
At the age of 3.8 years old the height was 85.9 cm (−3.76 SDS), weight 11.9 kg (−2.42 SDS), head circumference 50 cm (0.52 SDS), and growth velocity deflected at 5.29 cm/year (−1.80 SDS). Basal IGF-1 levels were 32 ng/ml (−2.28 SDS) and IGFBP-3 0.8 mcg/ml (2.0–4.5). After a high dose of rhGH (2.8 mg/mq/die: 1.6 mg/die for 7 days), stimulated IGF-1 levels were 62.0 ng/ml (−1.78 SDS) and IGF1BP-3 0.9 mcg/ml (2.0–4.5). We decided to start rhIGF-1 (0.5 mg twice daily s.c.: 0.04 mg/kg/twice daily).
In the hypothesis of a case of Laron Syndrome, we performed the direct sequencing of the complete coding sequence of GHR gene that revealed the presence of two heterozygous variation. The first is a missense mutation caused by the transition adenine to guanine (c.1A > G) in the first codon of exon 2. Given that, this substitution involved the translation initiation codon (Methionine) of the protein, the correct expression of the receptor will be necessary inhibited. The second variation is the substitution c.307G > A, that resulted in the replacement of the amino acid Aspartic Acid at position 103 to a residue of Asparagine (p.D103N), in exon 5 of the GHR sequence. This substitution involved the highly conserved Aspartic Acid 103 and, as predicted by the PolyPhen-2 Program (http://genetics.bwh.harvard.edu/pph2), it could be responsible for a damaging effect on GHR functionality. Due to the identification of these variations in her daughter, the parents underwent a molecular analysis for GHR gene mutation. The direct sequencing demonstrated that the father was heterozygous for the first codon mutation, whereas the mother was instead heterozygous for the p.D103N variation.