Precocious or early puberty in patients with combined pituitary hormone deficiency due to POU1F1 (PIT1) gene mutation Zehra YAVAS ABALI1, Firdevs BAŞ1, Şükran POYRAZOĞLU1, Rüveyde BUNDAK1, Feyza DARENDELİLER1 1Istanbul University, Istanbul Faculty of Medicine, Department of Pediatrics, Pediatric Endocrinology Unit, Istanbul, Turkey

BACKGROUND Arachnoid cyst, septo-optic dysplasia, brain tumors and cranial irradiation can cause combined pituitary hormone deficiency (CPHD). Central precocious puberty (CPP) has been reported in these cases. However, CPP is rare in CPHD caused by deficiency of pituitary transcription factors. Precocious puberty causes delays in the diagnosis of growth hormone (GH) deficiency and may have adverse effects on adult height. Aim To evaluate the early onset puberty in two patients with CPHD due to POU1F1 (PIT1) mutation.

Patient 1 Short stature at 18/12 years of age. He was born at term (birth weight: 0.6 SDS, birth length: -1.2 SDS). No perinatal asphyxia was noted. At 3 months of age central hypothyroidism was diagnosed and L-thyroxine replacement was started. Parents were first degree cousins. He had severe short stature (-6.6 SDS) and prepubertal on clinical evaluation without any dysmorphism. He had also GH and prolactin deficiency. Pituitary hypoplasia was detected on MRI. Puberty started at 7 9/12 years old with testicular enlargement and high LH level (1.2 mIU/ml) while he was on GH and L-thyroxine treatment. GnRH analogue was started at 8 years of age due to rapid progression of puberty and continued up to 11 years of age. In this patient with GH, TSH and prolactin deficiency a novel mutation was detected in POU1F1 gene (homozygote p.I244S) (Figure 1).

Patient 2 A six month old boy, was referred for growth retardation. He was born at term (birth weight: -1.0 SDS, birth length -0.8 SDS). He had no history of perinatal asphyxia. His parents were related. His weight and length were -1.9 and -2.7 SDS, respectively GH, TSH and prolactin deficiciency were detected. Homozygote (c.10C>T) POU1F1 gene mutation was detected (Figure 1). While he was on GH and L-thyroxine treatment, his puberty started before 10 years of age (bone age 12.5 years), relatively earlier with advanced bone age. At the age of 11 years GnRHa therapy was started due to rapid progression of puberty. Clinical and laboratory findings of the patients are summarized in the Table1, Table2 and Table3.

At admission Patient 1 Patient 2 Age at admission (months) 20 6 Gender M Birth weight (SDS) 0.6 -1.6 Weight (kg) (SDS) 6.8 (-3.5) 6.2 (-1.9) Height (cm) (SDS) 62 (-6.6) 60.5 (-2.7) Age of central hypothyroidism detection (months) 3 Peak GH levels (ng/ml) (ITT/clonidine) 3 / 1.6 0.12 / 0.08 Age of GH therapy initiation (months) 24 14

p.I244S 124 198 214 273 Q4X Patient 2 Patient 1 Figure 1. Mutations of the patients with CPHD due to POU1F1

At onset of puberty Patient 1 Patient 2 Age (years) 7 9/12 10 Height (SDS) -1.5 1.0 BMI (SDS) 1.3 2.1 Pubertal stage (Tanner) 2 Testis volume (ml) R/L (Prader) 4 / 4 Bone age (years) 8 12.5 Basal LH ( mIU/ml) 1.2 Basal FSH (mIU/ml) 2.9 1.8 Testosterone (ng/ml) 0.5 1.4 Target height (SDS) -2.9 -0.8 Predicted adult height (SDS) -1.6 -0.7 Age at GnRHa treatment initiation (years) 8.0 11.0

At recent evaluation Patient 1 Patient 2 Age (years) 19 12 Height (SDS) -1.9 1.2 BMI (SDS) 2.2 Testis volume (ml) R/L (Prader) 15 / 15 ml 5 / 5 ml Therapy L-thyroxine L-thyroxine, GH, GnRHa

Discussion Relation between POU1F1 gene and CPP or early puberty are not exactly explained in humans. In animal studies, it is reported that Pou1f1 gene has an important effect on regulation of GnRH receptor function and Gata2 gene. It has also been shown that this gene controls gonadotrope evolution and prevents excess gonadotropin levels (Figure 2). Further studies are needed to explain the relation between POU1F1 function and CPP.

Figure 2. Model of POU1F1 and GATA2 interaction

Conclusions CPP may occur in CPHD cases. However, exact mechanism of precocious puberty is not fully explained. Early puberty in GH deficiency complicates the follow up of growth and bone maturation. Advanced bone age due to precocious/early puberty has negative effect on adult height. It should be kept in mind that patients with hypothalamo-pituitary developmental anomalies may develop early puberty.

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