ESPE Abstracts

Introduction: Establishing a clear diagnosis in patients with short stature can be challenging. Careful examination and investigation of patients with short stature may identify additional features that help to make a diagnosis or direct genetic testing. We describe a patient with severe short stature with additional features on examination suggestive of KBG syndrome. A subsequent skeletal survey revealed radiological features suggestive of the diagnosis. In addition, the patient developed central precocious puberty (CPP) which has only been rarely reported in cohort studies of patients with KBG syndrome. KBG syndrome is most frequently caused by mutations in ANKRD11. The most significant clinical features include developmental delay, skeletal abnormalities and abnormal facies. We present a patient with a rare mutation in ANKRD11 with typical skeletal abnormalities and CPP.

Case presentation: A 5-year-old girl was referred for short stature with a background of autism, severe learning disability, sleep disturbance, bilateral hearing loss, constipation and abnormal hand movements. Birth weight was 3.2kg. Height was 96.9cm (-2.2 SDS), weight 14.8kg (+0.2 SDS), BMI 15.8. Maternal height was 150.4cm (-1.6 SDS) and paternal height 160.2cm (-2.2 SDS). Additional features included bilateral clinodactyly, foetal finger pads, broad toes, low hair line, mid facial hypoplasia, short neck, simple ears and macrodontia. Full blood count, urea and electrolytes, thyroid function tests and coeliac screen were all normal. IGF1 was elevated 195microg/L (34-172), although subsequently normalised by age 6 (227microg/L [31-343]). Skeletal survey revealed wormian bones, bilateral cervical ribs, and macrodontia. Bone age was delayed by 2.5 yrs. Genetic testing revealed a previously described de novo heterozygous ANKRND11 variant c.1903_1907del; p.(Lys635Glyfs*26). She then developed into puberty before age 8 years. LHRH test at 8.7 years showed a LH peak 6.3 IU/L, FSH peak 9.3 IU/L, in line with CPP. She commenced on GnRH-analogues.

Conclusion and learning points: ANKRND11 modulates chromatin, thereby affecting growth by increasing P21, a cell cycle inhibitor. The role of ANKRD11 in pubertal development is currently unknown. This case highlights clinical examination and radiological features that direct clinicians towards a diagnosis of KBG syndrome, including macrodontia and costovertebral abnormalities. CPP has been described rarely in patients with KBG syndrome but can be added to features that may help to direct to a diagnosis of KBG syndrome. Other syndromes with short stature and early puberty include Temple syndrome and Williams Syndrome.