This issue highlights Pediatric Endocrine Self-Assessment Program. Test your clinical knowledge and prepare for your exam. Available on the online store.
A 6-and-a-half-year-old boy presents for evaluation of short stature. He was growing along the 5th percentile until age 4 years. His birth history is unremarkable. His parents are of low-normal stature with a midparental target height of 65.4 in (166 cm) (–1.40 SDS, 8th percentile).
On physical examination, his weight is 37.5 lb (17 kg) (–2.08 SDS), height is 41.7 in (106 cm) (–2.42 SDS), and lower segment is 16.5 in (42 cm). The upper-to-lower segment ratio is 1.5. There is no evidence of scoliosis. Pubic hair is Tanner stage 1, and testicles are 2 mL in volume. Acanthosis nigricans is present on the neck. Hair and nails are normal.
Laboratory test results:
- IGF-1 = 159 ng/dL (20.8 nmol/L) (reference range, 38-253 ng/dL [5.0-33.1 nmol/L])
- Fasting glucose = 78 mg/dL (4.3 mmol/L) (reference range [fasting], 70-105 mg/dL [3.9-5.8 mmol/L])
- Fasting insulin = 6 μIU/mL (41.6 pmol/L) (reference range [fasting], 0-17 μIU/mL [0-118.1 pmol/L])
- Bone age is determined to be 6 years by the Greulich and Pyle method.
Which of the following is the most likely diagnosis?
- Acromesomelic dysplasia, Maroteaux type
- Cartilage-hair hypoplasia
- Rabson-Mendenhall syndrome
Activating mutations in the FGFR3 gene cause both achondroplasia and hypochondroplasia due to downstream activation of MAP kinase pathways that reduce the proliferation and differentiation of growth plate chondrocytes. Both conditions are associated with acanthosis nigricans, most likely due to the local effect of FGFR3 activating mutations on skin, not hyperinsulinemia. Both achondroplasia and hypochondroplasia are associated with short stature with near-normal growth of the trunk and head accompanied by short limbs leading to disproportionate short stature and an elevated upper-to-lower segment ratio. The average height of an adult with achondroplasia is 51.6 in (131 cm, –5.97 SDS) for males and 48.8 in (124 cm, –6.01 SDS) for females. The average height of an adult with hypochondroplasia is 57.5 in (146 cm, –4.07) for males and 54.3 in (138 cm, –3.87 SDS) for females. Because of the mild degree of this patient’s short stature, he most likely has hypochondroplasia (thus, Answer B is correct and Answer A is incorrect).
Acromesomelic dysplasia, Maroteaux type (Answer C), is caused by mutations in the NPR2 gene encoding the natriuretic peptide receptor B involved in growth and differentiation of growth plate chondrocytes. This disorder is associated with short-limbed short stature that is more severe than that observed in achondroplasia. Cartilage-hair hypoplasia (Answer D) is caused by mutations in the RMRP gene, which produces a noncoding RNA that is part of an enzyme complex called the mitochondrial RNA-processing endoribonuclease. Affected individuals have severe short-limbed short stature present at birth and sparse hair. Rabson-Mendenhall syndrome (Answer E) is a lipodystrophy caused by homozygous mutations in the INSR gene, which encodes the insulin receptor. It is associated with short stature, hirsutism, and acanthosis nigricans. Early in the course of this condition, children have hyperinsulinemic hypoglycemia followed by later insulin resistance with hyperglycemia and hyperinsulinemia. Because the child in this vignette has normal blood glucose and insulin levels, Rabson-Mendenhall syndrome is unlikely.
Distinguish between the disorders due to mutations in the fibroblast growth factor receptor 3 gene.
Alatzoglou KS, Hindmarsh PC, Brain C, Torpiano J, Dattani MT. Acanthosis nigricans and insulin sensitivity in patients with achondroplasia and hypochondroplasia due to FGFR3 mutations. J Clin Endocrinol Metab. 2009;94(10):3959-3963.
Gorden P, Zadeh ES, Cochran E, Brown RJ. Syndromic insulin resistance: models for the therapeutic basis of the metabolic syndrome and other targets of insulin resistance. Endocr Pract. 2012;18(5):763-771.
Pinto G, Cormier-Daire V, Le Merrer M, Samara-Boustani D, Baujat G, Fresneau L, et al. Efficacy and safety of growth hormone treatment in children with hypochondroplasia: comparison with an historical cohort. Horm Res Paediatr. 2014;82(6):355-363.