Isolated Growth Hormone Deficiency, Type V

A number sign (#) is used with this entry because of evidence that isolated growth hormone deficiency type V (IGHD5) is caused by compound heterozygous mutation in the RNPC3 gene (618016) on chromosome 1p21. One such family has been reported.

For general phenotypic information and a discussion of genetic heterogeneity of IGHD, see 262400.

Description

Isolated growth hormone deficiency type V is characterized by severe postnatal growth failure, delayed bone age without bone dysplasia, and hypoplasia of the anterior pituitary (Argente et al., 2014).

Clinical Features

Argente et al. (2014) reported 3 sisters, born with normal length to normal-statured nonconsanguineous parents, who developed severe postnatal proportionate growth retardation. They showed features typical of growth hormone (GH; see 139250) deficiency, including marked short stature, frontal bossing, cherubic face, mild microcephaly, delayed bone maturation without bone dysplasia, and otherwise normal development. GH levels after standard stimulation, as well as basal IGF1 (147440) and IGFBP3 (146732) levels, were almost undetectable. Pituitary hormone levels were in the low-normal to normal range, with brain MRI showing hypoplasia of the anterior pituitary. Total ghrelin levels were extremely elevated, with normal acylated ghrelin levels; no other biochemical abnormalities were found. The patients responded well to GH, with reduction of total ghrelin levels in all 3.

Martos-Moreno et al. (2018) provided follow-up on 3 Romanian sisters with GH deficiency originally described by Argente et al. (2014). In all 3 patients, treatment with recombinant human GH (rhGH) was highly effective despite the severity of their short stature, with increases in height between 4.0 and 5.9 SDS after 4.5 to 6.5 years on rhGH. In addition, lumbar spine bone mineral density improved and trabecular bone structure normalized. The oldest sister had onset of puberty shortly after starting treatment at 15.5 years of age, with menarche at age 16. However, she had oligomenorrhea despite pubertal levels of follicle-stimulating hormone (FSH; see 136530), luteinizing hormone (LH; see 152780), and estradiol, and a pubertal-shaped uterus with endometrium present on ultrasound. An intense lipolytic effect of rhGH treatment was also observed in the oldest sister, whose truncal obesity resolved completely in the first year of treatment, with body fat decreasing from 44% to 27%.

Molecular Genetics

In 3 sisters with isolated GH deficiency, in whom involvement of GH deficiency-associated and combined pituitary hormone deficiency-associated genes had been excluded, Argente et al. (2014) performed exome analysis and identified compound heterozygosity for a missense mutation (P474T; 618016.0001) and a nonsense mutation (R502X; 618016.0002) in the RNPC3 gene. The mutations segregated with disease in the family and were not found in 300 Spanish controls or in public variant databases.