Endocrine Abstracts

Introduction: Kallmann syndrome (KS) is a developmental disorder characterised by hypogonadotropic hypogonadism and anosmia. Known genetic causes account for up to 30% of patients with KS, with FGFR1 mutations being identified in 10%. FGFR1-related KS has an autosomal dominant inheritance with incomplete penetrance. We present a family with KS due to a novel variably penetrant FGFR1 mutation, where the presenting features included cleft lip/palate and anosmia.

Case presentation: A 9-year-old girl (proband) was referred to the Endocrinology Department with short stature, cleft lip and later anosmia. Her height was 122.9 cm (SDS −1.29; MPH 68th centile) with weight 23.1 kg (SDS −1.3); she was prepubertal. Laboratory tests showed undetectable LH and FSH, with normal concentrations of other pituitary hormones. MRI showed structurally normal pituitary gland and olfactory bulbs. Her 6-year-old brother presented with previously repaired cleft lip and palate, short stature and later anosmia. His height was 110.5 cm (SDS −1.18) with weight 18.2 kg (SDS −1.36). He had normal prepubertal genitalia, with testicular volumes of 2 ml. Basal pituitary function was normal. MRI revealed a small anterior pituitary. Molecular analysis revealed a heterozygous deletion, c.915delG, in exon 8 of FGFR1 in both siblings, resulting in a truncated protein, p.[Glu305AspfsTer17], that is not present on the ExAC Browser. It was inherited from their father who had normal height (SDS 1.23) and fertility, although his puberty was late. The proband was still prepubertal at age 11.5 years, with poor growth. Additional investigations included a glucagon stimulation test with normal response (peak GH 29.3 mcg/l) and GnRH stimulation test with LH and FSH peaks of 1.4 U/l and 1.3 U/l, respectively. Oestradiol was undetectable. She started treatment with ethinyloestradiol, with subsequent pubertal development and improved growth. She also had an audiogram that revealed mild conductive hearing loss. Her brother is currently 11 years old and is growing normally (height velocity 4.9 cm/yr). A GnRH test will be performed at the appropriate age.

Discussion: This case reflects the clinical heterogeneity of KS due to FGFR1 mutations. In KS, other developmental anomalies can occur, including renal agenesis, skeletal anomalies, hearing impairment, and cleft lip/palate, the latter occurring in 25–30% of patients with FGFR1-related KS. Here, both siblings presented with cleft lip or palate, and the proband had conductive hearing loss. Interestingly, they also both developed café au lait spots; whether this is an unreported feature of FGFR1 mutations is uncertain.