GLI2 variant associated with hypopituitarism and midline defects

Magnacavallo Anna Lia; Giulia Sterpetti; Ilaria Polenzani; Rossella Mascaro; Angela Errico; Carmen Bucolo; Carla Meroni Silvia Laura; Graziano Barera; Pozzobon Gabriella Cinzia

Pituitary stalk interruption syndrome (PSIS) can be classified as a form of holoprosencephaly. The sonic hedgehog signaling (SHH) has a key role in central nervous system midline development. GLI2 is a transcription factor of SHH pathway. GLI2 pathogenetic variants show phenotypic variability and nonpenetrance. We present a female patient born at 37+1 weeks of gestation from moroccans non-consanguineous parents. Unicogenic. Polihydramnios, urogenital sinus, palatal and lip cleft were identified by ultrasound imaging at the third trimester of gestation. Karyotype and CGH-array were normal. TORCH screens were negative. Birth weight of 2670g. The initial examination revealed complete palatal and lip cleft, female external genitalia, common opening of urethra and vagina with anteriorized anus. Postnatally, she was transferred to the Neonatal Intensive Care Unit and required intravenous supplementation of glucose and electrolytes. Within the first 48 hours after birth she developed non-isoimmune hyperbilirubinemia that resolved with phototherapy. From the fourth day of life nasogastric tube feeding was started. The cranial MRI showed a PSIS: ectopic neurohypophysis with pituitary stalk agenesis and anterior pituitary hypoplasia. The abdominal MRI confirmed urogenital sinus persistence associated with left renal agenesis and right calico-pyelic dilatation. An endocrinology assessment was made:

Table 1
TSH	5.85 mcU/mL	0.25-5
FT4	Not dosed	0.92-1.99
LH	< 0.3 mU/ml	0.1-6
FSH	< 0.3 mU/ml	1.4-18.1
GH	0.38 mcg/L	0-5
IGF1	< 15 mcg/L	15-200
Cortisol	3 mcg/L	48-195
ACTH	11 ng/L	7-28
Cortisol after ACTH stimulation test (dose unknown)	44 mcg/L

At 5 months old she was referred to our center for an endocrinological revaluation. Weight 5.468 Kg (-1.77 standard deviation score (SDS)). Lenght 56.6 cm (- 3.19 SDS). ACTH, TSH and GH deficiencies were diagnosed. No evidence of minipuberty.

Table 2
TSH	4.45 mcIU/ml	0.25-5
FT4	0.48 ng/dl	0.92-1.99
IGF1	Not detectable (mcg/L)	15-200
FSH	< 0.3 mU/ml	1.4-18.1
LH	< 0.3 mU/ml	0.1-6
Estradiol	< 5 pg/ml	< 27
Cortisol	15 ng/ml	48-195
ACTH	26 pg/ml	7-28
Cortisol after ACTH stimulation test (80 mcg)	111 ng/ml

Hormone replacement therapy was started with hydrocortisone, levothyroxine and recombinant biosynthetic GH. An NGS panel of genes linked to panhypopiuitarism was performed and detected a VUS of GLI2 c.1495C>T in heterozygous. GLI2 analysis in parents is ongoing. Our case can contribute to expand the knowledge on GLI2 variants related phenotypes. During the next generation sequencing era, understand the genotype-phenotype correlation can allow a rapid diagnosis.

ESPE Abstracts

P3-123