ESPE Abstracts (2018) 89 P-P1-200

PROKR2 Mutations in Patients with Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiency

Adam Najaflıa, Firdevs Başb, Birsen Karamana, Aslı Derya Kardelen Alb, Güven Toksoya, Şükran Poyrazoğlub, Oya Uygunera, Şahin Avcıa, Umut Altunoğlua, Esin Karakılıç Özturanb, Seher Başarna & Feyza Darendelilerb


aIstanbul University, Medical Genetics, Istanbul, Turkey; bIstanbul University, Pediatric Endocrinology, Istanbul, Turkey


Background: Rokineticin receptors (PROKR1 and PROKR2) belong to the family of G protein-coupled receptors. Bi-or mono allelic mutations in PROKR2 gene have been identified in Kallmann syndrome which is characterized by hypogonadotropic hypogonadism and anosmia/hyposmia. Recently, PROKR2 mutations were reported in patients with multiple pituitary hormone (MPHD) and growth hormone deficiencies (GHD), suggesting a potential role for the PROK2 pathway in pituitary development, in addition to its role in GnRH neuron development.We present here clinical and molecular findings of one patient with MPHD and two patients with GHD.

Patients and methods: Patient-1 and Patient-2 were presented with short stature and Patient-3 was diagnosed with central hypothyroidism at age of 5 months and started on L-T4 replacement therapy and referred for further endocrinological evaluation. Clinical features of the patients are summarized in Table 1. There were no dysmorphic findings in the patients. Six months after presentation, Patient-1 and -2 showed a low height velocity and growth hormone (GH) stimulation tests were performed. GHD was diagnosed and GH replacement therapy was started. Patient-1 has not yet been completed pubertal development; Patient-2 has completed pubertal development and had menarche at age of 15 years. Patient-3 is still prepubertal. This patient was suspected to have hypogonadotropic hypogonadism without anosmia because of low gonadotropin levels, bilateral cryptorchidism and micropenis at presentation. Prolactin level was 1.9 ng/ml. GH treatment was started at age of 2.2 years and orchiopexy was done at age of 2.7 years. Chromosomal abnormalities were excluded before the admission of molecular genetic analysis. Screening of targeted regions for in-house designed short stature panel with 25 genes revealed two different heterozygous clinical variants previously reported with Kalmann syndrome in each patient in PROKR2 gene.

Table 1 Some clinical and laboratory findings of the patients.
At presentationPatient 1Patient 2Patient 3
Age (year)12110.5
Gender FemaleFemaleMale
Consanguinity3rd degree1st degreeNone
Birth weightSDS−2.00.7−0.6
HeightSDS−2.8−2.5−3.3
Pubertal stage Ph1B2/2Ph1B2/2Ph1T0.5/0.5 ml
Bone age (year)810/12−10710/12-810/12-
Target heightSDS−2.4−0.7−0.9
At recent evaluation
Age (year)13.318.410
HeightSDS−2.6−1.72.4
Pubertal stageA3Ph3B4/4A3Ph5B5/5A2Ph2Testis 2/2ml
Bone age (year)1116
Hormonal deficienciesGHGHGH-TSH-PRL
MRI (Cranialand pituitary)NormalNormalNormal
PROKR2 NM_144773.2 NP_658986.1c.254G>A p.Arg85Hisc.254G>A p.Arg85Hisc.518T>G p.Leu173Arg

Conclusion: Heterozygous PROKR2 mutations should be kept in mind as a very rare cause GHD and MPHD.